WO1997012030A1 - Apparatus and methods for active programmable matrix devices - Google Patents
Apparatus and methods for active programmable matrix devices Download PDFInfo
- Publication number
- WO1997012030A1 WO1997012030A1 PCT/US1996/014353 US9614353W WO9712030A1 WO 1997012030 A1 WO1997012030 A1 WO 1997012030A1 US 9614353 W US9614353 W US 9614353W WO 9712030 A1 WO9712030 A1 WO 9712030A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hybridization
- biochip
- dna
- sample
- detection
- Prior art date
Links
Classifications
-
- G—PHYSICS
- G11—INFORMATION STORAGE
- G11C—STATIC STORES
- G11C13/00—Digital stores characterised by the use of storage elements not covered by groups G11C11/00, G11C23/00, or G11C25/00
- G11C13/0002—Digital stores characterised by the use of storage elements not covered by groups G11C11/00, G11C23/00, or G11C25/00 using resistive RAM [RRAM] elements
- G11C13/0009—RRAM elements whose operation depends upon chemical change
- G11C13/0014—RRAM elements whose operation depends upon chemical change comprising cells based on organic memory material
- G11C13/0019—RRAM elements whose operation depends upon chemical change comprising cells based on organic memory material comprising bio-molecules
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
- B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y10/00—Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
- C07K1/045—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers using devices to improve synthesis, e.g. reactors, special vessels
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
- C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
- C12Q1/6816—Hybridisation assays characterised by the detection means
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
- C12Q1/6816—Hybridisation assays characterised by the detection means
- C12Q1/6825—Nucleic acid detection involving sensors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
- C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
- C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
-
- G—PHYSICS
- G11—INFORMATION STORAGE
- G11C—STATIC STORES
- G11C13/00—Digital stores characterised by the use of storage elements not covered by groups G11C11/00, G11C23/00, or G11C25/00
- G11C13/0002—Digital stores characterised by the use of storage elements not covered by groups G11C11/00, G11C23/00, or G11C25/00 using resistive RAM [RRAM] elements
- G11C13/0009—RRAM elements whose operation depends upon chemical change
- G11C13/0014—RRAM elements whose operation depends upon chemical change comprising cells based on organic memory material
-
- G—PHYSICS
- G11—INFORMATION STORAGE
- G11C—STATIC STORES
- G11C19/00—Digital stores in which the information is moved stepwise, e.g. shift registers
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
- H01L25/00—Assemblies consisting of a plurality of individual semiconductor or other solid state devices ; Multistep manufacturing processes thereof
- H01L25/50—Multistep manufacturing processes of assemblies consisting of devices, each device being of a type provided for in group H01L27/00 or H01L29/00
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00279—Features relating to reactor vessels
- B01J2219/00306—Reactor vessels in a multiple arrangement
- B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
- B01J2219/00315—Microtiter plates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00279—Features relating to reactor vessels
- B01J2219/00306—Reactor vessels in a multiple arrangement
- B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
- B01J2219/00315—Microtiter plates
- B01J2219/00317—Microwell devices, i.e. having large numbers of wells
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00497—Features relating to the solid phase supports
- B01J2219/00527—Sheets
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00585—Parallel processes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/0059—Sequential processes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00596—Solid-phase processes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
- B01J2219/00612—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports the surface being inorganic
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
- B01J2219/00614—Delimitation of the attachment areas
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
- B01J2219/00614—Delimitation of the attachment areas
- B01J2219/00621—Delimitation of the attachment areas by physical means, e.g. trenches, raised areas
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
- B01J2219/00623—Immobilisation or binding
- B01J2219/00626—Covalent
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
- B01J2219/00632—Introduction of reactive groups to the surface
- B01J2219/00637—Introduction of reactive groups to the surface by coating it with another layer
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00639—Making arrays on substantially continuous surfaces the compounds being trapped in or bound to a porous medium
- B01J2219/00644—Making arrays on substantially continuous surfaces the compounds being trapped in or bound to a porous medium the porous medium being present in discrete locations, e.g. gel pads
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00653—Making arrays on substantially continuous surfaces the compounds being bound to electrodes embedded in or on the solid supports
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00659—Two-dimensional arrays
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/0068—Means for controlling the apparatus of the process
- B01J2219/00686—Automatic
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/0068—Means for controlling the apparatus of the process
- B01J2219/00686—Automatic
- B01J2219/00689—Automatic using computers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00709—Type of synthesis
- B01J2219/00713—Electrochemical synthesis
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
- B01J2219/0072—Organic compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
- B01J2219/0072—Organic compounds
- B01J2219/00722—Nucleotides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
- B01J2219/0072—Organic compounds
- B01J2219/00725—Peptides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
- B01J2219/0072—Organic compounds
- B01J2219/00731—Saccharides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00819—Materials of construction
- B01J2219/00824—Ceramic
- B01J2219/00828—Silicon wafers or plates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00851—Additional features
- B01J2219/00853—Employing electrode arrangements
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/0095—Control aspects
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/0095—Control aspects
- B01J2219/00952—Sensing operations
- B01J2219/00968—Type of sensors
- B01J2219/0097—Optical sensors
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/02—Adapting objects or devices to another
- B01L2200/025—Align devices or objects to ensure defined positions relative to each other
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/14—Process control and prevention of errors
- B01L2200/143—Quality control, feedback systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0627—Sensor or part of a sensor is integrated
- B01L2300/0636—Integrated biosensor, microarrays
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0627—Sensor or part of a sensor is integrated
- B01L2300/0645—Electrodes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0832—Geometry, shape and general structure cylindrical, tube shaped
- B01L2300/0838—Capillaries
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
- B01L2300/0877—Flow chambers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
- B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
- B01L2400/0421—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic electrophoretic flow
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L9/00—Supporting devices; Holding devices
- B01L9/52—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
- B01L9/527—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips for microfluidic devices, e.g. used for lab-on-a-chip
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/11—Compounds covalently bound to a solid support
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/10—Libraries containing peptides or polypeptides, or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/12—Libraries containing saccharides or polysaccharides, or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
- C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
-
- G—PHYSICS
- G11—INFORMATION STORAGE
- G11C—STATIC STORES
- G11C13/00—Digital stores characterised by the use of storage elements not covered by groups G11C11/00, G11C23/00, or G11C25/00
- G11C13/04—Digital stores characterised by the use of storage elements not covered by groups G11C11/00, G11C23/00, or G11C25/00 using optical elements ; using other beam accessed elements, e.g. electron or ion beam
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
- H01L2224/00—Indexing scheme for arrangements for connecting or disconnecting semiconductor or solid-state bodies and methods related thereto as covered by H01L24/00
- H01L2224/01—Means for bonding being attached to, or being formed on, the surface to be connected, e.g. chip-to-package, die-attach, "first-level" interconnects; Manufacturing methods related thereto
- H01L2224/26—Layer connectors, e.g. plate connectors, solder or adhesive layers; Manufacturing methods related thereto
- H01L2224/31—Structure, shape, material or disposition of the layer connectors after the connecting process
- H01L2224/32—Structure, shape, material or disposition of the layer connectors after the connecting process of an individual layer connector
- H01L2224/321—Disposition
- H01L2224/32151—Disposition the layer connector connecting between a semiconductor or solid-state body and an item not being a semiconductor or solid-state body, e.g. chip-to-substrate, chip-to-passive
- H01L2224/32221—Disposition the layer connector connecting between a semiconductor or solid-state body and an item not being a semiconductor or solid-state body, e.g. chip-to-substrate, chip-to-passive the body and the item being stacked
- H01L2224/32225—Disposition the layer connector connecting between a semiconductor or solid-state body and an item not being a semiconductor or solid-state body, e.g. chip-to-substrate, chip-to-passive the body and the item being stacked the item being non-metallic, e.g. insulating substrate with or without metallisation
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
- H01L2224/00—Indexing scheme for arrangements for connecting or disconnecting semiconductor or solid-state bodies and methods related thereto as covered by H01L24/00
- H01L2224/01—Means for bonding being attached to, or being formed on, the surface to be connected, e.g. chip-to-package, die-attach, "first-level" interconnects; Manufacturing methods related thereto
- H01L2224/42—Wire connectors; Manufacturing methods related thereto
- H01L2224/44—Structure, shape, material or disposition of the wire connectors prior to the connecting process
- H01L2224/45—Structure, shape, material or disposition of the wire connectors prior to the connecting process of an individual wire connector
- H01L2224/45001—Core members of the connector
- H01L2224/45099—Material
- H01L2224/451—Material with a principal constituent of the material being a metal or a metalloid, e.g. boron (B), silicon (Si), germanium (Ge), arsenic (As), antimony (Sb), tellurium (Te) and polonium (Po), and alloys thereof
- H01L2224/45138—Material with a principal constituent of the material being a metal or a metalloid, e.g. boron (B), silicon (Si), germanium (Ge), arsenic (As), antimony (Sb), tellurium (Te) and polonium (Po), and alloys thereof the principal constituent melting at a temperature of greater than or equal to 950°C and less than 1550°C
- H01L2224/45144—Gold (Au) as principal constituent
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
- H01L2224/00—Indexing scheme for arrangements for connecting or disconnecting semiconductor or solid-state bodies and methods related thereto as covered by H01L24/00
- H01L2224/01—Means for bonding being attached to, or being formed on, the surface to be connected, e.g. chip-to-package, die-attach, "first-level" interconnects; Manufacturing methods related thereto
- H01L2224/42—Wire connectors; Manufacturing methods related thereto
- H01L2224/47—Structure, shape, material or disposition of the wire connectors after the connecting process
- H01L2224/48—Structure, shape, material or disposition of the wire connectors after the connecting process of an individual wire connector
- H01L2224/481—Disposition
- H01L2224/48151—Connecting between a semiconductor or solid-state body and an item not being a semiconductor or solid-state body, e.g. chip-to-substrate, chip-to-passive
- H01L2224/48221—Connecting between a semiconductor or solid-state body and an item not being a semiconductor or solid-state body, e.g. chip-to-substrate, chip-to-passive the body and the item being stacked
- H01L2224/48225—Connecting between a semiconductor or solid-state body and an item not being a semiconductor or solid-state body, e.g. chip-to-substrate, chip-to-passive the body and the item being stacked the item being non-metallic, e.g. insulating substrate with or without metallisation
- H01L2224/48227—Connecting between a semiconductor or solid-state body and an item not being a semiconductor or solid-state body, e.g. chip-to-substrate, chip-to-passive the body and the item being stacked the item being non-metallic, e.g. insulating substrate with or without metallisation connecting the wire to a bond pad of the item
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
- H01L2224/00—Indexing scheme for arrangements for connecting or disconnecting semiconductor or solid-state bodies and methods related thereto as covered by H01L24/00
- H01L2224/01—Means for bonding being attached to, or being formed on, the surface to be connected, e.g. chip-to-package, die-attach, "first-level" interconnects; Manufacturing methods related thereto
- H01L2224/42—Wire connectors; Manufacturing methods related thereto
- H01L2224/47—Structure, shape, material or disposition of the wire connectors after the connecting process
- H01L2224/48—Structure, shape, material or disposition of the wire connectors after the connecting process of an individual wire connector
- H01L2224/484—Connecting portions
- H01L2224/4847—Connecting portions the connecting portion on the bonding area of the semiconductor or solid-state body being a wedge bond
- H01L2224/48472—Connecting portions the connecting portion on the bonding area of the semiconductor or solid-state body being a wedge bond the other connecting portion not on the bonding area also being a wedge bond, i.e. wedge-to-wedge
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
- H01L2224/00—Indexing scheme for arrangements for connecting or disconnecting semiconductor or solid-state bodies and methods related thereto as covered by H01L24/00
- H01L2224/73—Means for bonding being of different types provided for in two or more of groups H01L2224/10, H01L2224/18, H01L2224/26, H01L2224/34, H01L2224/42, H01L2224/50, H01L2224/63, H01L2224/71
- H01L2224/732—Location after the connecting process
- H01L2224/73251—Location after the connecting process on different surfaces
- H01L2224/73265—Layer and wire connectors
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
- H01L2924/00—Indexing scheme for arrangements or methods for connecting or disconnecting semiconductor or solid-state bodies as covered by H01L24/00
- H01L2924/095—Indexing scheme for arrangements or methods for connecting or disconnecting semiconductor or solid-state bodies as covered by H01L24/00 with a principal constituent of the material being a combination of two or more materials provided in the groups H01L2924/013 - H01L2924/0715
- H01L2924/097—Glass-ceramics, e.g. devitrified glass
- H01L2924/09701—Low temperature co-fired ceramic [LTCC]
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
- H01L2924/00—Indexing scheme for arrangements or methods for connecting or disconnecting semiconductor or solid-state bodies as covered by H01L24/00
- H01L2924/30—Technical effects
- H01L2924/301—Electrical effects
- H01L2924/3011—Impedance
Definitions
- This invention relates to devices and systems for performing multi-step molecular biological type diagnostic analyses in multiplex formats. More particularly, the molecular biological type analyses include various nucleic acid hybridizations reactions and associated biopolymer synthesis. Additionally, antibody/antigen reactions and other clinical diagnostics can be performed.
- Molecular biology comprises a wide variety of techniques for the analysis of nucleic acid and protein. Many of these techniques and procedures form the basis of clinical diagnostic assays and tests. These techniques include nucleic acid hybridization analysis, restriction enzyme analysis, genetic sequence analysis, and the separation and purification of nucleic acids and proteins
- the complete process for carrying out a DNA hybrid ⁇ ization analysis for a genetic or infectious disease is very involved. Broadly speaking, the complete process may be divided into a number of steps and substeps (see Figure 1) .
- the first step involves obtaining the sample (blood or tissue) . Depending on the type of sample, various pre-treatments would be carried out.
- the second step involves disrupting or lysing the cells, which then release the crude DNA material along with other cellular constituents. Gener ⁇ ally, several sub-steps are necessary to remove cell debris and to purify further the crude DNA. At this point several options exist for further processing and analysis.
- a third option involves denaturing the purified sample DNA and carrying out a direct hybridization analysis in one of many formats (dot blot, microbead, microliter plate, etc.) .
- a second option called Southern blot hybrid ⁇ ization, involves cleaving the DNA with restriction enzymes, separating the DNA fragments on an electrophoret ⁇ ic gel, blotting to a membrane filter, and then hybrid ⁇ izing the blot with specific DNA probe sequences. This procedure effectively reduces the complexity of the genomic DNA sample, and thereby helps to improve the hybridization specificity and sensitivity. Unfortunately, this procedure s long and arduous.
- a third option is to carry out the polymerase chain reaction (PCR) or other amplification procedure.
- the PCR procedure amplifies (increases) the number of target DNA sequences. Amplifi ⁇ cation of target DNA helps to overcome problems related to complexity and sensitivity in genomic DNA analysis. All these procedures are time consuming, relatively compli ⁇ cated, and add significantly to the cost of a diagnostic test. After these sample preparation and DNA processing steps, the actual hybridization reaction is performed. Finally, detection and data analysis convert the hybridization event into an analytical result.
- samples have been obtained through any number of means, such as obtaining of full blood, tissue, or other biological fluid samples.
- the sample is processed to remove red blood cells and retain the desired nucleated (white) cells. This process is usually carried out by density gradient centrifugation. Cell disruption or lysis is then carried out, preferably by the technique of sonication, freeze/thawing, or by addition of lysing reagents.
- Nucleic acid hybridization analysis generally involves the detection of a very small number of specific target nucleic acids (DNA or RNA) with an excess of probe DNA, among a relatively large amount of complex non-target nucleic acids.
- the substeps of DNA complexity reduction in sample preparation have been utilized to help detect low copy numbers (i.e. 10,000 to 100,000) of nucleic acid targets.
- DNA complexity is overcome to some degree by amplification of target nucleic acid sequences using polymerase chain reaction (PCR) .
- PCR polymerase chain reaction
- amplification results in an enormous number of target nucleic acid sequences that improves the subsequent direct probe hybridization step
- amplification involves lengthy and cumbersome procedures that typically must be performed on a stand alone basis relative to the other substeps.
- Substantially complicated and relatively large equipment is required to perform the amplification step.
- the actual hybridization reaction represents the most important and central step in the whole process.
- the hybridization step involves placing the prepared DNA sample in contact with a specific reporter probe, at a set of optimal conditions for hybridization to occur to the target DNA sequence.
- Hybridization may be performed in any one of a number of formats. For example, multiple sample nucleic acid hybridization analysis has been conducted on a variety of filter and solid support formats
- the micro-formatted hybridization can be used to carry out "sequencing by hybridization” (SBH) (see M. Barinaga, 253 Science, pp. 1489, 1991; W. Bains, 10 Bio/Technology, pp. 757-758, 1992) .
- SBH makes use of all possible n-nucleotide oligomers (n-mers) to identify n- mers in an unknown DNA sample, which are subsequently aligned by algorithm analysis to produce the DNA sequence
- the first format involves creating an array of all possible n- mers on a support, which is then hybridized with the target sequence.
- the second format involves attaching the target sequence to a support, which is sequentially probed with all possible n-mers .
- Both formats have the fundamen ⁇ tal problems of direct probe hybridizations and additional difficulties related to multiplex hybridizations.
- Southern United Kingdom Patent Application GB 8810400, 1988; E. M. Southern et al . , 13 Genomics 1008, 1992, proposed using the first format to analyze or sequence DNA. Southern identified a known single point mutation using PCR amplified genomic DNA. Southern also described a method for synthesizing an array of oligonucleotides on a solid support for SBH. However, Southern did not address how to achieve optimal stringency condition for each oligonucleotide on an array.
- Drmanac et al . 260 Science 1649-1652, 1993, used the second format to sequence several short (116 bp) DNA sequences.
- Target DNAs were attached to membrane supports ("dot blot" format) .
- Each filter was sequentially hybridized with 272 labelled 10-mer and li ⁇ mer oligonucleotides.
- a wide range of stringency condition was used to achieve specific hybridization for each n-mer probe; washing times varied from 5 minutes to overnight, and temperatures from 0°C to 16°C. Most probes required 3 hours of washing at 16°C.
- the filters had to be exposed for 2 to 18 hours in order to detect hybridiza- tion signals.
- the overall false positive hybridization rate was 5% in spite of the simple target sequences, the reduced set of oligomer probes, and the use of the most stringent conditions available.
- an excitation energy of one wavelength is delivered to the region of interest and energy of a different wavelength is reemitted and detected.
- Large scale systems generally those having a region of interest of two millimeters or greater, have been manufactured in which the quality of the overall system is not inherently limited by the size requirements of the optical elements or the ability to place them in optical proximity to the region of interest.
- the conventional approaches to fluorometer design have proved inadequate.
- the excitation and emission optical elements must be placed close to the region of interest.
- a focused spot size is relatively small, often requiring sophisticated optical designs.
- the size of the optical components required to achieve these goals in relation to their distance from the region of interest becomes important, and in many cases, compromises the performance obtained. Accordingly, a need exists for an improved fluorescent detection system.
- the present invention relates to the design, fabrica ⁇ tion, and uses of a self-addressable self-assembling microelectronic devices and systems which can actively carry out controlled multi-step processing and multiplex reactions in a microscopic formats. These reactions include, but are not limited to, most molecular biological procedures, such as nucleic acid hybridization, anti ⁇ body/antigen reaction, and related clinical diagnostics.
- the claimed devices and systems are able to carry out multi-step combinatorial biopolymer synthesis, including, but not limited to, the synthesis of different oligonucleotides or peptides at specific micro-locations on a given device.
- the claimed devices and systems are fabricated using both microlithographic and micro-machining techniques.
- the basic device has a matrix of addressable microscopic locations on its surface; each individual micro-location is able to control electronically and direct the transport and attachment of specific binding entities (e.g., nucleic acids, enzymes, antibodies) to itself. All micro- locations can be addressed with their specific binding entities.
- specific binding entities e.g., nucleic acids, enzymes, antibodies
- the self-addressing process requires minimal outside intervention in terms of fluidics or mechanical components.
- the device is able to control and actively carry out a variety of assays and reactions. Analytes or reactants can be transported by free field electrophoresis to any specific micro-location where the analytes or reactants are effectively concentrated and reacted with the specific binding entity at the micro-location.
- the sensitivity for detecting a specific analyte or reactant is improved because hybrid ⁇ ization reactants are concentrated at a specific micro ⁇ scopic location. Any un-bound analytes or reactants can be removed by reversing the polarity of a micro-location.
- APEX devices which stands for addressable programmable electronic matrix.
- the APEX device is utilized with a fluidic system in which a sample is flowed over the APEX device during operation.
- the fluidic system includes a flow cell and a liquid waste containment vessel.
- the sample is provided to the input to the flow cell and directed across the active areas of the APEX system.
- a defined volume is provided within the flow cell, preferably in the range from 5 to 10 microliters.
- a flowing sample over the active detection device provides important advantages in the hybridization analysis of dilute, concentrated and/or relatively complex DNA samples. For example, if the total sample volume is relatively large compared to the same chamber volume, flowing of the sample provides more complete analysis of the entire sample. Alternatively, where the sample volume is relatively small, and/or the DNA is relatively concentrated, dilution is indicated in order to reduce the viscosity of the sample.
- additional processing steps or substeps may be performed in sequence with a " system" .
- the system is an integrated arrangement of component devices. Each component device is appropri ⁇ ately designed and scaled to carry out a particular function.
- a system may perform all aspects of sample preparation, hybridization and detection and analysis.
- the sample is first prepared, such as by an electronic cell sorter component.
- electronic refers more specifically to the ability of the component device to electrophoretically transport charged entities to or from itself.
- Further DNA processing and complexity reduction may optionally be performed by a crude DNA selector component, and a restriction fragment selector component.
- the final processed target DNA is transported to the analytical component where electronic hybridization analysis is carried out in a microscopic multiplex format.
- This analytical component device is also referred to as the APEX or analytical chip.
- Associated detection and image analysis components provide the results.
- an electronic reagent dispenser component can provide electrophoretic transport of reagents to the various processing components of the system.
- an electronic waste disposal system may be formed by providing an electrode and charged matrix material that attracts and holds charged waste products.
- an electronic DNA fragment storage system can serve to temporarily hold other DNA fragments for later hybridiza ⁇ tion analysis.
- genomic DNA complexity reduction is performed by processes that isolate those specific DNA fragments containing the desired target sequence from the bulk of the DNA material that lacks the desired target sequence. Crude DNA can be transported and captured on a support material . The bound DNA can then be severed using appropriate restriction enzymes. After severing, the DNA fragments can be transported to a component device that selectively hybridizes specific DNA fragments. Those fragments that contain the actual target sequences to be analyzed can be selectively released, via further restriction enzyme cleavage, and transported to the analytical component (APEX chip) of the system. Optionally, this procedure may be repeated for other fragments containing other target sequences.
- APEX chip analytical component
- a controller for the device provides for individual control of various aspects of the device.
- the controller permits individual microlocations to be controlled electronically so as to direct the transport and attachment of specific binding entities to that location.
- the device may carry out multi-step and multiplex reactions with complete and precise electronic control, preferably under control of a microprocessor based component. The rate, specificity, and sensitivity of multi-step and multiplex reactions are greatly improved at the specific microlocations on the device.
- the controller interfaces with a user via input/output devices, such as a display and keyboard input.
- a graphical user interface is adapted for ease of use.
- the input/output devices are connected to a controller, which in turn controls the electrical status of the addressable electronic locations on the system. Specifically, the controller directs a power supply/waveform generator to generate the electronic status of the various microlocations.
- an interface is used between the power supply/waveform generator and the APEX device or system.
- the interface preferably comprises a bank of relays subject to the controller via a multifunction input/output connection.
- the relays preferably serve to connect the power supply/waveform generator to the APEX device by controlling the connection as to its polarity, the presence or absence of a connection and the amount of potential or current supply to the individual location.
- the controller preferably controls the illumination source directed at the hybridization system.
- a detector, image processing and data analysis system are optically coupled to the APEX device.
- a fluorescent microscope receives and magnifies the image from the hybridization events occurring on the various micro-locations of the device.
- the emissions are optically filtered and detected by a charge coupled device (CCD) array or microchannel plate detector.
- CCD charge coupled device
- the image is then stored and analyzed. Preferably, the results are displayed to the user on the monitor.
- a light transfer member such as an optical fiber
- a fiber optic is coaxially arranged in a liquid light guide.
- An excitation source such as a laser, provides radiation through optics such that the excitation fiber delivers the excitation radiation to the region of interest.
- the excitation fiber is disposed axially within the return light guide path, at least at the proximal end adjacent the region of interest .
- the return path preferably comprises a liquid light guide preferably including optics to receive emission from the region of interest, and to transfer that emission through the light guide to the detector.
- the hybridiza- tion system is formed having a plurality of microlocations formed atop a substrate containing control electronics. Specifically, switching circuits are provided to address individually the microlocations. The electrical connec ⁇ tions are made via the backside relative to where sample contact is to be made. Additionally, an optical pathway, such as a waveguide, is disposed beneath the microlocation to permit backside access to the microlocation. Optical excitation, if necessary, may be directed to the microlocation via the waveguide. Detection of emitted radiation may be detected via the backside waveguide.
- a sample containment system is disposed over the system, particularly the hybridization matrix region. In the preferred embodiment, the matrix hybridization region (including sample contain- ment component) is adapted for removal from the remainder of the device providing the electronic control and detec ⁇ tor elements.
- a substrate such as silicon
- an insulating layer such as a thick oxide.
- Conductive microlocations are formed, such as by deposition of metal (e.g., aluminum or gold) that is then patterned, such as by conventional photo-lithographic techniques.
- An insulating coating is formed, such as TEOS formed by PECVD.
- a nitride passivation coating is formed over the TEOS layer. Openings to the microelectrode are formed through the nitride and glass.
- adhesion improving materials such as titanium tungsten may be utilized in connection with the metal layer to promote adhesion to the oxide and/or glass .
- wells may be formed atop of the electrode by undercutting a nitride layer disposed on an oxide layer supported by the substrate.
- Electronic control of the individual microlocations may be done so as to control the voltage or the current .
- the other may be monitored.
- the current may be moni ⁇ tored.
- the voltage and/or current may be applied in a direct current mode, or may vary with time.
- pulsed currents or DC biases may be advantageously utilized.
- the pulsed system may be advantageously uti ⁇ lized with the fluidic system, especially the flow cell design. By coordinating the pulse sequence and flow rate, the sample can be more effectively interrogated throughout the sample volume. Additionally, even for non-flow situations, such as where there are relatively high amounts of non-target material, e.g., DNA, which without pulsing might overwhelm the activated test sites. Pulse techniques generally result in higher target mobility rates at higher ionic strength, reduced probe burn-out effects, improved hybridization efficiencies, improved discrimination of point mutations and enhanced DNA fingerprinting.
- the fluorescence signal obtained during the electronic denaturation of DNA hybrids is perturbed at or around electronic and power levels which are associated with dehybridization.
- the fluorescence signal perturbation results in a rise or spike in fluorescence intensity prior to dehybridization of fluorescently labelled probes from a capture sequence attached to an APEX pad.
- the power level, amplitude and slope of this fluorescence spike provide analytical tools for diagnosis.
- the combination of the fluorescence perturbation with other measurements also indicative of the hybridization match/mismatch state, such as consideration of the electronic melting (50% fluorescence decrease during electronic stringency control) can in combination provide a more efficient and reliable hybridization match/mismatch analysis.
- Fluorescently labelled fragments having a given length would be attached to a capture probe at a test site.
- a reverse potential would be applied to the test site in an amount sufficient to determine the amount of binding between the capture probe and the labelled fragment.
- Those DNA having longer length will be selectively dehybridized at lower electronic current levels.
- the dehybridization current level correlates with DNA size.
- Fig. 1 shows the sequence of steps and substeps for sample preparation, hybridization and detection and data analysis.
- Figs. 2A and 2B show the active, programmable matrix system in cross-section (Fig. 2A) and in perspective view (Fig. 2B) .
- Fig. 3 shows the active, programmable matrix system structure at the metal mask layer.
- Fig. 4 shows detail of the active, programmable matrix system in plan view.
- Fig. 5 shows a perspective view of a single microlocation and electrical connection.
- Fig. 6 shows a cross-sectional view of a fluidic system including a flow cell in combination with the APEX device.
- Fig. 7 shows a plan view of a fluidic system in ⁇ cluding a flow cell and liquid waste containment system in combination with the diagnostic system on a PCMCIA board.
- Fig. 8 shows a plan view of the system including an electronic cell sorter matrix, DNA selectors and restric ⁇ tion fragment selectors and hybridization matrix.
- Fig. 9 shows a block diagram description of the control system.
- Fig. 10 shows user displays for various voltage and current regimes .
- Fig. 11 shows a cross-sectional view of a fluorescence detection system useful for small geometry systems.
- Fig. 12A is a plot of the relative fluorescent intensity as a function of applied power (microwatts) for a 20-mer oligomer duplex (100% AT) .
- Fig. 12B is a plot of the relative fluorescent intensity versus applied power (microwatt) for a 19-mer oligomer duplex (53% GC) .
- Fig. 13A is a graph of the relative fluorescent intensity versus applied power (microwatt) for a 20-mer oligomer duplex (100% AT) .
- Fig. 13B is a plot of the relative fluorescent intensity versus applied power (microwatt) for a 19-mer oligomer duplex (53% GC) .
- Fig. 14A shows a cross-sectional view of a mismatched test site having a capture probe, target DNA and a reporter probe.
- Fig. 14B is a cross-sectional view of target DNA and a reporter probe with a associated fluorophore.
- Fig. 14C is a graph of the fluorescent response graphing the relative fluorescent intensity as a function of time for a pulsed sequence.
- Fig. 15A is a cross-sectional view of a matched test site having a capture probe, target DNA and a reporter probe with an intercalcated fluorophore.
- Fig. 15B is a cross-sectional view of target DNA and a reporter probe with an intercalcating fluorophore.
- Fig. 15C is a graph of the fluorescent response showing the relative fluorescence intensity as a function of time for a pulsed sequence.
- Fig. 16A-D are cross-sectional views of multiple test sites of a electronic stringency control device utilized for DNA fingerprinting and analysis.
- Figs. 2A and 2B illustrate a simplified version of the active programmable electronic matrix hybridization system for use with this invention.
- a substrate 10 supports a matrix or array of electronically addressable microlocations 12.
- the various microlocations in Fig. 2A have been labelled 12A, 12B, 12C and 12D.
- a permeation layer 14 is disposed above the individual electrodes 12. The permeation layer permits transport of relatively small charged entities through it, but precludes large charged entities, such as DNA, from contacting the electrodes 12 directly.
- the permeation layer 14 avoids the electrochemical degradation which would occur in the DNA by direct contact with the electrodes 12. It further serves to avoid the strong, non-specific adsorption of DNA to electrodes.
- Attachment regions 16 are disposed upon the permeation layer 14 and provide for specific binding sites for target materials. The attachment regions 16 have been labelled 16A, 16B, 16C and 16D to correspond with the identification of the electrodes 12A-D, respectively.
- reservoir 18 comprises that space above the attachment regions 16 that contains the desired, as well as undesired, materials for detection, analysis or use.
- Charged entities 20, such as charged DNA are located within the reservoir 18.
- the active, programmable, matrix system comprises a method for transporting the charged material 20 to any of the specific microlocations 12.
- a microlocation 12 When activated, a microlocation 12 generates the free field electrophoretic transport of any charged functionalized specific binding entity 20 towards the electrode 12. For example, if the electrode 12A were made positive and the electrode 12D negative, electrophoretic lines of force 22 would run between the electrodes 12A and 12D. The lines of electro ⁇ phoretic force 22 cause transport of charged binding entities 20 that have a net negative charge toward the positive electrode 12A.
- the electrophoretic transport generally results from applying a voltage which is sufficient to permit electrolysis and ion transport within the system. Electrophoretic mobility results, and a current flows through the system, such as by ion transport through the electrolyte solution. In this way, a complete circuit may be formed via the current flow of the ions, with the re ⁇ mainder of the circuit being completed by the conventional electronic components, such as the electrodes and controlled circuitry.
- the voltage which induces electrolysis and ion transport is greater than or equal to approximately 1.2 volts .
- attachment layers which are not subject to reaction, such as 16B and 16C by making their corresponding electrodes 12B and 12C negative.
- electrophoretic lines of force emanating from the attachment region 16B (only 16B will be discussed for simplicity, the results being similar for 16C) .
- the electrophoretic force lines 24 serve to drive away nega ⁇ tively charged binding entities 20 from the attachment layer 16B and towards the attachment layer 16A. In this way, a "force field" protection is formed around the attachment layers 16 which it is desired to have nonreac- tive with the charged molecules 20 at that time.
- charged binding materials 20 may be highly concentrated in regions adjacent to signal attachment layers 16.
- FIG. 2B if a individual microlocation 26A is positively charged, and the remaining microlocation are negatively charged, the lines of electrophoretic force will cause transport of the net negatively charged binding entities 20 toward the microlocation 26A.
- the microlocation 26A is intended to depict the combination in Fig. 2A of the attachment layer 16, the permeation layer 14 and the underlying associated electrode 12. In this way, a method for concentrating and reacting analytes or reactants at any specific microlocation on the device may be achieved.
- the underlying microelectrode 12 may continue to function in a direct current (DC) mode.
- DC direct current
- This unique feature allows relatively dilute charged analytes or reactant molecules free in solution to be rapidly transported, concentrated, and reacted in a serial or parallel manner at any specific micro-location that is maintained at the opposite charge to the analyte or reactant molecules.
- This ability to concentrate dilute analyte or reactant molecules at selected microlocations 26 greatly accelerates the reaction rates at these microl ⁇ ocations 26.
- the electrode 12 may have its potential reversed thereby creating an electrophoretic force in the direction opposite to the prior attractive force. In this way, nonspecific analytes or unreacted molecules may be removed from the microlocation 26.
- Specific analytes or reaction products may be released from any microlocation 26 and transported to other locations for further analysis,* or stored at other addressable locations; or removed completely from the system. This removal or deconcentra ion of materials by reversal of the field enhances the discrimination ability of the system by resulting in removal of nonspecifically bound materials.
- electronic stringency control may be achieved. By raising the electric potential at the electrode 12 so as to create a field sufficient to remove partially hybridized DNA sequences, thereby permitting identification of single mismatched hybridizations, point mutations may be identi ⁇ fied.
- Operations may be conducted in parallel or in series at the various attachment layers 16.
- a reaction may occur first at attachment layer 16A utilizing the potentials as shown.
- the potential at electrode 12A may be reversed, that is, made negative, and the potential at the adjacent electrode 12B may be made positive.
- a series reactions occurs.
- Materials that were not specifically bound to attachment layer 16A would be transported by electropho ⁇ retic force to attachment layer 16B.
- the concentration aspect is utilized to provide high concen- trations at that specific attachment layer then subject to the positive electrophoretic force.
- the concentrated materials may next be moved to an adjacent, or other, attachment layer 16.
- multiple attachment layers 16 may be deprotected in the sense that there is a net electrophoretic force field emanating from the elec ⁇ trode 12 through the attachment layer 16 out into the reservoir 18. By deprotecting multiple attachment layer 16, multiplex reactions are performed.
- Each individual site 26 may serve in essence as a separate biological "test tube" in that the particular environment addressed by a given attachment layer 16 may differ from those environments surrounding the other attachment layers 16.
- Fig. 3 shows a plan view of the metal mask layer for an active programmable electronic matrix system.
- a plurality of individual electrodes 30 are formed preferably in an array. For example, an 8 x 8 matrix of individual electrodes 30 is formed.
- additional control or dump pads 32 may be provided to aid in generation of desired electrophoretic fields.
- the electrodes 30 and pad 32 are connected to contact pads 34.
- 68 contact pads 34 are shown corresponding to the 64 elec- trodes 30 and 4 pads 32.
- Leads 36 connect the electrodes 30 and pads 32 individually to the contacts 34.
- a fan-out pattern is used to permit connections from the relatively condensed region of the electrodes 30 and pads 32 to the boundaries 36 of the mask.
- Fig. 4 shows an exploded detail plan view of the mask of Fig. 3.
- the resulting metallized system would appear substantially similar to the masked pattern.
- the elec ⁇ trodes 30 are shown formed as substantially square struc- tures.
- the lead lines 36 connect the electrode 30 to the contact pad 34 (Fig. 3) .
- the preferred line width of the lead 36 is 1 to 20 microns.
- Fig. 5 shows a perspective view of a single electrode 50.
- the electrode 50 is connected directly to the lead 52.
- a permeation layer 54 is disposed above the lead 50.
- An attachment layer 56 is disposed upon the permeation layer 54.
- the permeation layer in microlithographically pro ⁇ quiz devices can range in thickness from 1 nm to 1,000 micrometers, with 500 nm to 100 micrometers being the most preferred.
- the permeation layer should cover the entire electrode surface.
- the permeation layer may be formed from any suitable material such as polymers, membranes, porous metal oxides (e.g., aluminum oxide) , ceramics, sol- gels, layered composite materials, clays and controlled porosity glass .
- Fig. 6 shows a cross-sectional view of a fluidic system in combination with a APEX like detection system.
- Fig. 7 shows a plan view of the fluidic system of Fig. 6 in the larger environment of its inclusion on a printed circuit board. Reference numbers will be utilized in comment to the extent possible.
- a biochip 60 preferably an APEX type chip as described above, is combined with a fluidic system.
- the fluidic system includes a flow cell 62.
- the flow cell 62 is disposed adjacent and above the biochip 60, and preferably in hermetic contact with the biochip 60.
- the flow cell 62 preferably includes an aperture 64 which permits optical access to the biochip 60.
- a flow cell window 66 contacts the flow cell 62 at the peripheral edges of the flow cell window 66.
- the flow cell window may be a quartz, or other suitable material chose in part for its transmission and non-fluorescence properties.
- the flow cell window 66 is chosen to have an index of refraction which substantially matches the index of refraction of the sample solution.
- An inlet port 68 and an outlet port 70 are provided through the flow cell 62.
- a sample chamber 74 is defined by the combination of the flow cell 62, the flow cell window 66 and the biochip 60. In the preferred embodiment, the sample chamber 74 has a volume from approximately 5 to approximately 10 microliters.
- An input tube 76 is preferably connected to the input port 68.
- the input tube 76 connects to a fluidic interface port 78, such as formed by a female Luer taper system.
- An output tube 80 is preferably connected to the outlet port 70.
- the components of the fluidic system are preferably formed from inert materials, e.g., tetrafluoroethylene, or other medical grade plastics.
- the flow cell 62 and associated components may be formed through any known technique, such as molding or machining.
- the output tube 80 preferably provides a communication path from the flow cell 62 to a reservoir 82.
- the reservoir 82 has a minimum volume of approximately 1.2 ml.
- the reservoir 82 is formed as a generally nonexpandable waste tube.
- the waste tube reservoir 82 is filled by the fluid flow from the flow cell 62 through the output tube 80.
- the reservoir 82 may be an expandable structure, such as an expandable mylar bag.
- the reservoir 82 may optionally operate under vacuum, thereby providing additional force to cause the sample to flow into the reservoir 82.
- Such a vacuum structure may be formed such as through a vacutainer.
- the biochip 60 is preferably mounted on a printed circuit board 84, such as a FR4 circuit board, via adhe ⁇ sive 86.
- the adhesive 86 may be of any type conventional used in the surface mount technology art, and may be either conductive or nonconductive as desired.
- the adhesive 86 may be a thermally conductive epoxy.
- Lead wires 88 connect from the biochip 60 to the printed leads 90. Conventional techniques such as ball bonding or wedge bonding using 0.001 inch AlSi or gold wire may be used.
- the printed leads 90 are formed on the printed circuit board through conventional techniques. As shown in Fig. 7, the printed circuit board is formed in the PCMCIA format, such that a 68 position electrical contact 92 provides an interface between the printed leads 90 and the electronics connected to the electrical contact 92. Other conventional formats may be used.
- the lead wires 88 are potted or encapsulated in a protective material 94, such as nonconductive UV resistant epoxy.
- the protective material 94 provides electrical insulation for the lead wires 88, provides a moisture barrier for the lead wires 88 and provides mechanical support for overall device ruggedness. Overall rigidity of the printed circuit board 84 and structures formed thereon is generated by the optional frame 96.
- the biochip 60 is preferably attached via adhesive 86 to the printed circuit board 84.
- lead wires 88 are connected from the biochip 60 to the printed leads 90.
- the lead wires 88 are then encapsulated in the protective material 94, with the central region of the biochip 60 disposed outward from the adhesive 86 being kept clear. In the APEX device the clear region is approximately 7.5 mm 2 .
- the flow cell 62 is then directly bonded to the biochip 60.
- the flow cell 62 may be formed of any material compatible with the purposes and materials described, such as medical grade plastic.
- the biochip 60 may be formed, such as from silicon.
- the flow cell 62 may then be attached to the silicon of the biochip 60 by adhesives, which would generally be relatively thin.
- the order of affixing the flow cell 62 to the biochip 60 and the encapsulating of the lead wires in the 88 in the protective material 94 may be reversed, namely the flow cell 62 or components thereof may be affixed to the biochip 60 prior to the addition of the protective material 94.
- the biochip 60 is placed at the center of rotational gyration of the structure of Fig. 7.
- the biochip 60 includes a permeation layer or other layer disposed at the surface of the biochip 60. These materials are often spin-coated onto the surface of the biochip 60.
- the completed structure of Fig. 7, excluding the flow cell window 66, and optionally excluding other components, e.g., the frame 96, the input tube 76, the fluidic interface port 78, the output tube 80 and the reservoir 82 may be spun so as to add the materials to the surface of the biochip 60.
- the spin rates can often be relatively large, for example, 10,000 rpm for the spin-coating of certain polymers, placing the biochip 60 at the center of rotation provides for easier spin-coating.
- a generic device of the type shown in Fig. 7 may be formed, and the suitable polymers and capture sequences for an assay placed down as desired.
- Fig. 8 shows a complete system 100 for the automated sample preparation and hybridization of prepared materi ⁇ als.
- a sample 102 such as blood or other biological materials are introduced into the system 100.
- a sample addition port 104 is provided.
- the sample addition port 104 is utilized when an overlying biological containment structure is present such that the sample 102 could not be directly placed into the system without access via the port 104.
- a containment cover 106 such as glass or transparent plastic, may be disposed over the system 100.
- Sample preparation is performed in this system 100 by the combination of the electronic cell sorter matrix component 108 and DNA selector component 110 and restric- tion fragment selector component 112.
- the selector component 112 may be further characterized based upon its intended use, such as a restriction fragment selector 112 or to isolate bacterial or viral nucleic acids from human genomic or background DNA.
- the electronic cell sorter matrix component 108 consists of underlying electrodes, with permeation layers and an attachment layers. These effectively form a matrix of locations for the attachment of cells. Generally, the area for individual locations and the complete matrix area are larger than the areas in an analytical device component. Thus, the electronic cell sorter matrix is scaled appropriately to accommodate variation in the number of cells from different samples and sample sizes.
- the attachment layers can be generally selective for cells, or individual selective for different types of cells. Optionally, groups or sets of locations can be made selective for one type of cell. Cell selectivity can be imparted by attaching specific antibodies or cell adhesion factors to the attachment layer.
- the matrix 108 operates by free field electrophore- sis.
- the crude DNA selector 110 and selector 112 serve to bind the crude DNA output from the electronic cell sorter matrix 108 and permit selective cleavage of the desired DNA from the bound material.
- the term crude is used merely to denote a non-final stage in DNA isolation or complexity reduction.
- the DNA is bound to the selector in a region which is believed not to contain the desired DNA material .
- the desired DNA materials are then severed from the bound materials, such as by application of restriction enzymes.
- the selector 112 would be designed to isolate bacterial or viral nucleic acids from human genomic or other background DNA.
- the severed, unbound material is then physically moved from the crude DNA selector 110 to the selector 112.
- electrophoretic transport is used to remove the severed material . This process may be repeated by binding the severed material to a selector, upon which a restriction enzyme acts so as to cleave the unbound portion which contains the desired DNA.
- human DNA contains approximately 100,000 genes. Of the total DNA material, a significant portion constitutes repeating sequences which do not contain the desired DNA information.
- the DNA may be bound to a selec ⁇ tor by these noninformation bearing repeating sequences.
- the bound DNA may be severed from the unbound DNA which is believed to contain the desired DNA to be analyzed. This process may then be repeated with yet more specific se ⁇ quences causing binding of the material to the selector.
- the output of the selector 112 is then supplied to the APEX chip 114. Operations on the matrix 114 are performed as described in connection with Figs. 2A and 2B.
- An electronic reagent dispenser system 116 may be provided to deliver reagents to the system 100. Preferably, the reagents are delivered by electrophoretic force if they are charged.
- an electronic waste disposal system 118 is included within the system 100. The waste disposal system 118 attracts charged waste particles to it and disposes of them by holding the charged entities on it.
- Another optional member of system 100 is the DNA fragment storage system 120. This fragment storage system 120 serves to temporarily hold DNA fragments for future analysis.
- auxiliary electrodes 122 may be provided in the system 100.
- the auxiliary electrodes 122 may assist in the electrophoretic motion of materials throughout the system 100. By providing selective acti ⁇ vation of the auxiliary electrodes 122 along the long axis, the motion of the materials may be aided or inhib ⁇ ited.
- fluid input and output ports 124 serve to provide additional addition of fluids to the system 100.
- electrical connections 126 are shown disposed around the system 100 and serve to provide electrical contact, such as to the driver board/computer interface 138 (Fig. 9) .
- the system 100 may include some or all of the func ⁇ tions described above.
- the combination of sample preparation in the form of complexity reduction, as performed by the DNA selector 110 and restriction fragment selector 112 may be associated with the analytical matrix 114.
- any or all of the above described functions may be combined as desired.
- Fig. 9 shows a block diagram of the overall system including the controller 130.
- the underlying electrodes in an APEX device are made active by the application of a controlled potential to the electrode or by the sourcing of a controlled current through the electrode. Full functionality is realized when the potential or current at each electrode of the APEX device is independently controlled. This is accomplished by an APEX controller system.
- the controller computer 130 interfaces with user input/output devices, such as a display 132 and input device 134.
- the display 132 may be any form of conventional display such as a monitor or computer screen.
- the input 134 may be any conventional user input device, such as a keyboard, mouse, or touch-screen device.
- the controller computer 130 is connected with the power supply and waveform generator 136.
- the controller 130 sets the power supply and waveform generator 136 to provide the current or voltage output to the interface 138.
- the power supply or waveform gen- erator 136 is capable of providing precisely regulated and voltage and current sourcing.
- the controller computer 80 provides control signals to the interface 138 via the multifunction input/output board 140.
- the interface 138 provides a simplified connection to the contacts for the APEX system 142.
- the interface preferably includes relays that permit selective connection between the power supply and waveform generator 136 to the specific electrodes of the APEX system 142.
- the interface 138 comprises a plurality of relays which connect the power supply and waveform generator 136 to the APEX system 142 electrodes. The connections permit the selection or non-selection of a path between the power supply and waveform generator 136 to the APEX system 142 electrodes.
- another relay permits selecting the polarity of the voltages supplied to the APEX system 142 electrodes.
- the specific level to be connected to an APEX system 142 electrode may be set independently of those for the other electrodes.
- the interface 138 may serve to select the desired voltage for the individual electrodes in the APEX system 142. Alternatively, such a different voltage arrangement may be achieved through use of a voltage divider.
- the controller computer 130 is a Macintosh Quadra 950.
- National Instruments Corporation LabVIEW software is used to provide a software interface for a user to program the devices connected to the APEX and to collect and process data from an assay.
- National Instruments NuBus boards are used to provide the hardware interface from the Quadra 950 computer 130 to the power supply devices 136 that source potentials and cur ⁇ rents and that measure the actual currents and potentials and the results of the assay.
- the user controls the assay through a Virtual Instru ⁇ ment created with the LabVIEW software.
- the virtual instrument provides a user friendly graphical representa ⁇ tion of the controls that the user may exercise, and of some of the results of applying these controls to the APEX device to perform an assay.
- the user interfaces with the Virtual Instrument through the keyboard and mouse (collec- tively, input 134) of the Quadra 950 computer 130.
- the Virtual Instrument provides software interfaces to a National Instruments NB-MIO-16XL multipurpose input/output 140 and to a National Instruments DMA2800 board that are connected to the NuBus data bus of the Quadra 950.
- the multipurpose I/O board is able to provide digital and/or analog signals to external devices to implement the programmed sequence specified by the user through the Virtual Instrument.
- the MIO board is also able to digitize and store in the Quadra 950, under control of the Virtual Instrument, signals generated by the devices connected to the APEX.
- the DMA2800 provides the ability to store rapidly the data acquired by the MIO board through Direct Memory Access, bypassing the Quadra 950 CPU.
- the DMA 2800 also provides a GPIB (IEEE 488) inter- face for control of external devices that adhere to the IEEE 488 communication and data transfer standard, which includes most modern instruments. In this preferred embodiment of the controller, two external devices are used to source the potentials or currents to the APEX.
- a Keithley 236 Source/Measure Unit power supply 86 provides adequate stability and flexibility as a source of precisely regulated potential or current.
- the SMU 236 either applies a potential and measures the resultant current or provides a source of current and measures the resultant potential.
- This device is programmed from the Virtual Instrument under GPIB control through the DMA2800 board to control the current or potential levels and time dependence, and to measure and store the actual potentials and currents that are sourced to the APEX.
- the sourced currents or potentials are applied to the APEX through an array of relays in interference 138 that provide independent switching of each electrode between no connection, connection to positive source and connection to negative source.
- the preferred embodiment also provides for more than one Source/Measure supply to be utilized to provide different levels of positive and negative potential or current to different electrodes.
- the array of relays is provided by a National Instruments SCXI Chassis with nine 16-channel, Class 3 Relay Modules connected in the chassis, providing a total of 144 relays. Two relays are used per electrode to provide for electrode disconnected or electrode connected to either positive or negative source.
- a bundle of cables connects these relays to the APEX device through a Cerprobe Probe Card that provides mechanical contact of probes to the bond pads of the APEX device.
- the controller computer 130 optionally controls the illumination source 144 for excitation of fluorescence to detect DNA hybridization.
- the illumination source 144 is a laser which outputs radiation at an appropriate wavelength to excite fluo ⁇ rescent markers included within the APEX system 142.
- the output of the APEX system 142 is passed through observation path 146 to the detector 148.
- the observation path 146 may be a physical connection, such as through a fiber optic, or may comprise an optical path such as through a microscope. Optical filters may be utilized in the observation path to reduce illumination of the detector at wavelengths not corresponding to the emission spectra of the fluorescent markers in the APEX system 142.
- notch filters may be utilized as necessary to reduce illumination of the detector 148 at the excitation wavelength of the laser illumination source 144.
- the detector 148 may optionally form an image of the APEX system 142, such as through the use of a cooled CCD camera.
- the emitted fluorescence radiation from the APEX system 142 may be detected by conventional means such as photodiodes or photomultiplier tubes.
- the output of the detector 148 is provided to the data processing/analysis system 150. This system monitors the level of detected probe material in the APEX system 142.
- an expert system may be utilized in the analysis system 150.
- a Data Translation Frame Grabber board is interfaced to the Quadra 950 NuBus, to provide capture to memory of images recorded by video cameras such as the Optronics cooled color CCD camera used in the preferred embodiment.
- This CCD camera observes the APEX device through a microscope with appropriate filters to provide visualization of fluorescence on the APEX array.
- Alternate systems may implement all the functionality of the controller as described, but may use custom devices incorporated into printed circuit boards and custom soft ⁇ ware to control the board with a similar user-friendly interface for programming the device. These alternate systems may also incorporate the switching elements of the array of relays into a semiconductor device underlying the active, programmable matrix system.
- the permeation layer (e.g., layer 14 of Fig. 2) may be formed from materials such as, but not exclusive to, membranes, metal oxides (e.g., aluminum oxide) , carbon chain polymers, carbon-silicon chain polymers, carbon- phosphorous chain polymers, carbon-nitrogen chain poly ⁇ mers, silicon chain polymers, polymer alloys, layered polymer composites, interpenetrating polymer materials, ceramics, controlled porosity glass, materials formed as sol-gels, materials formed as aero-gels, materials formed as hydro-gels, porous graphite, clays or zeolites.
- membranes e.g., metal oxides (e.g., aluminum oxide)
- carbon chain polymers e.g., carbon-silicon chain polymers, carbon- phosphorous chain polymers, carbon-nitrogen chain poly ⁇ mers, silicon chain polymers, polymer alloys, layered polymer composites, interpenetrating polymer materials, ceramics, controlled porosity glass, materials formed as sol-
- Permeation layers separate the binding entities from the surface of the electrode.
- Micro-locations have been created using microlithographic and micro-machining tech ⁇ niques.
- the permeation layer may be disposed within a well (see, e.g., Fig. 2A) or may not be recessed and simply be coated with a permeation layer covering the electrodes. Either of these arrangements may be formed by spin coating of the permeation layer.
- Chemical modification of the surface of the micro-locations and of polymer layers over the micro-locations have been used to create specialized attachment sites for surface func ⁇ tionality.
- Mesh type permeation layers involve random arrangements of polymeric molecules that form mesh like structures having an average pore size determined by the extent of cross-linking.
- DNA capture probe was attached to the surface of the permeation layer by a Schiff base reaction between an oxidized ribonucleoside attached to the DNA capture probe and the primary amine of the poly-1-lysine. This provides evidence of covalent attachment of special functionality to the surface of the permeation layer.
- An oxidized DNA capture probe was brought to a surface micro-location by electrophoretic transport.
- the capture probe was labeled with a fluorescent marker. This demonstrates the ability to address a micro-location by electrophoretic transport.
- the maximum DC current density that was attained at a gold micro-location, which was not modified with a permeation layer, before bubbles due to water hydrolysis appeared was 8 milliampheres/cm2.
- the maximum DC current density that was attained at a gold micro-location, which was modified by an acrylamide-based permeation layer, before bubbles due to water hydrolysis appear was 40 milliampheres/cm2. This demonstrates the ability of the permeation layer to raise the maximum accessible current density before bubbles form due to water hydrolysis.
- An ionomer sandwich permeation layer is formed from one or more lamina of polyelectrolytes .
- the polyelectrolyte layers may have the same charge, different charge, or may be charge mosaic structures.
- a two layer ionomer sandwich layer was formed from a base layer of a perfluorinated sulfonic acid polyelectro- lyte (Nafion) and an upper layer of poly-1-lysine.
- the base Nafion layer was cast onto a micro-location and allowed to dry. This base layer was then exposed to a 1% by weight aqueous solution of poly-1-lysine.
- the cationic lysine-based polymer adsorbed strongly to the anionic Nafion base layer.
- the poly-1-lysine layer allowed the attachment of an oxidized DNA capture probe to the surface of the permeation layer by a Schiff base reaction.
- the Nafion base layer is anionic and is permselective toward negative ions such as DNA.
- Fig. 10 shows examples of the graphical user inter ⁇ face.
- Window 160 shows an overall view of the display.
- Identification information 162 is provided.
- the various pads of the active, programmable matrix system are identi ⁇ fied in a rectangular coordinate system.
- the displays 164 each show the electrical parameter, such as current or voltage for particular pads.
- Box 164A shows the current as a function of time for a pad, (3,4) , wherein the current varies as a function of time, changing directions during the course of the application.
- Box 164B shows a pad, (3,5) , having no applied current during the time shown.
- Box 164C shows a time varying current for pad (4,4) , wherein that current is delayed with respect to time relative to the pad (3,4) reported in Box 164A.
- Box 164D shows a pad, (4,5) , with no applied current as a function of time.
- Box 164E shows a pad, (1,1) , for which the voltage has a constant, negative DC value.
- Box 164F shows the voltage as a function of time for a pad, (3,4) having a more negative DC value. In all cases, the boxes show the programmed current or voltage as a dotted line, and the measured current or voltage as a solid line.
- the electric field that gives rise to ion migration may be modulated in time as long as a DC bias voltage or current is applied simultaneously.
- the use of an AC signal superimposed on a DC bias voltage or current can achieve three things, 1) minimize the background due to nonspecifically bound DNA, 2) provide a means of electronic stringency control where the control variable is the frequency of the alternating current or voltage, 3) provide a means of aligning DNA molecules spatially.
- FIG. 11 shows a cross-sectional view of an improved detection system.
- a sample 170 includes a region of interest 172.
- the region of interest 172 may include multiple areas on the sample 170.
- Any of the various excitation sources 174 and detectors 176 as are conventionally used in fluormetric systems may be utilized with this invention.
- the excitation fiber 178 is preferably fiber optic light guide.
- the excitation fiber 178 has an input end 180 and an output end 182.
- the output end 182 may be formed in a manner as known to those skilled in the art so as to provide focused projection of the energy from the excitation source 174.
- Optional fiber launch system optics 184 receive the output of the excitation source 174 and provide the radiation to the input end 180 of the excitation fiber 178.
- the light guide 186 preferably comprises a liquid light guide portion 188.
- the liquid light guide 188 is surrounded by a housing 190, which serves to contain the liquid light guide 188.
- a proximal lens 192 is disposed within the housing 190 at that portion of the light guide 186 which is disposed towards the region of interest 172.
- a distal end 194 is disposed within the housing 190 at the end of the light guide 186 disposed towards the detector 176.
- the excitation fiber 178 is formed coaxially in the light guide 186.
- the output end 182 of the excitation fiber 178 is disposed through aperture 196 in the proximal lens 192.
- the radiation from the excitation source 174 may be supplied through the excitation fiber 178 and delivered to the region of interest 172 without passing through the optical components of the proximal lens 192.
- the output end 182 of the excitation fiber 178 may be disposed within the liquid light guide 188 such that the radiation of the excitation source 174 passes through the optical component of the distal lens 194 before being supplied to the region of interest 172.
- the use of the excitation fiber 178 such as when a fiber optic, permits a degree of mechanical decoupling between the excitation source 174 and the sample 170.
- the excitation source 174 and the detector 176 may be fixed in place while the light guide 186 and excitation fiber 178 are moved over the sample 170.
- the excitation fiber 178 includes an axially region 198 which is disposed along the axis of rotation of the light guide 186. This concentric axial alignment of the optical paths of the axial region 198 of the excitation fiber 178 and the light guide 186 provide for alignment to the detector 176.
- the liquid light guide 188 advantageously provides for more complete transference of the energy from the region of interest 172 to the detector 176.
- fiber bundles may be utilized in the light guide 186, though the liquid light guide 188 provides more complete coverage of the output from the proximal lens 192.
- the APEX device as described previously has been utilized in novel ways resulting in method which improve the analytical or diagnostic capabilities of the device. It has been surprisingly discovered that the fluorescent signal is perturbed during the electronic denaturation of DNA hybrids. This method has particular application to DNA hybridization and single-base mismatch analysis. Specifically, during electronic denaturation, also known as stringency control, a rise or spike in the fluorescence intensity has been observed just prior to the dehybridization of the fluorescent labelled probes from capture sequences attached to the APEX chip pad.
- Figs. 12A and 12B show the results of electronic denaturization experiments run on an APEX chip having 25 test microlocations with 80 micron diameter utilizing platinum electrodes. For this use, the chip was overlaid with a 1 micron thick avidin/agarose permeation layer. Two 5' -labeled bodipy Texas Red (Ex 590 nm, EM 630 nm) target probes were used in the experiments.
- the probe of Fig. 12A was a 20 mer (5' -BYTR-AAATTTTAATATATAAT-3 ' ) containing 100% AT, with a melting temperature (Tm) of 33°C.
- Tm melting temperature
- Tm melting temperature
- the appropriate complementary biotinylated capture sequences were attached to the avidin/agarose permeation layer over several of the test pads (on the same chip) .
- the capture probe density was -10 8 probes per pad.
- the fluorescent labeled target probes, at a concentration of -1.0 ⁇ M in 50 mM sodium phosphate (pH 7.0) , 500 mM NaCl were first hybridized to the attachment probes on the 5580 chips. The chips were then thoroughly washed with 20 mM NaP04 (pH 7.0) .
- Electronic denaturation was then carried out by biasing the test pad negative, and increasing the power to the test pad from -10 "1 microwatts ( ⁇ W) to -2 x IO 2 microwatts ( ⁇ W) over a 90 second time period. Three pads were tested for each of the target probes. The relative change in fluorescent intensity was plotted as a function of the increasing power.
- the electrophoretic force or power necessary to de-hybridize a probe from its complementary sequence correlates with the binding energy or Tm (melting temperature) for the DNA duplex.
- Figs. 13A and 13B show the results of denaturation experiments run on the APEX chip having 25 test microlocations with 20 micron deep wells to the underlying platinum electrodes.
- the well structures on the chip were filled with avidin/agarose composite, forming a 20 micron deep permeation layer.
- the same fluorescent target probes, capture probes and protocols were used in the deep well experiments as in the operation of the device resulting in the information of Figs. 12A and 12B.
- the overall power ( ⁇ W) necessary to de-hybridize the 19-mer probe with 53% GC (Tm of 54°C)
- the 20-mer probe with 100% AT Tm of 33°C)
- the slope for the 100% AT probe is much shallower, then for the 53% GC probe.
- the fluorescent perturbation/spike phenomena is very pronounced for the 19-mer probe with 53% GC in the deep well experiments.
- the fluorescent perturbation phenomena correlates well with the sequence specificity of the dehybridization process.
- the power level ( ⁇ W) value, amplitude and slope of the fluorescent spike are useful for many aspects of hybridization analysis including single base mismatch analysis.
- the fluorescent perturbation (Fp) value namely those values associated with the fluorescence perturbation, e.g., onset value, peak height and slope, combined with the electronic melting (Em) values, namely, the half-height value of fluorescence, provide significantly higher reliability and additional certainty to hybridization match/mis-match analysis. By combining two or more analytical measurements, a more effective and precise determination may be made.
- the target probes were labeled with a Bodipy Texas Red fluorophore in their 5' terminal positions. While Bodipy TR is not a particularly environmentally sensitive fluorophore it nevertheless showed pronounced effects during electronic denaturation. More environmentally sensitive fluorophores may be used to obtain larger perturbations in their fluorescent properties during electronic de-hybridization.
- an intercalcating fluorophore 200 may be disposed between a reporter probe 202 and target DNA 204.
- Fig. 14A shows the condition in which the reporter probe 202 is mismatched from the target DNA 204 by a mismatched base 206.
- the capture probe 208 serves to capture the target DNA 204, with the pad 210 providing the electrophoretic action.
- the intercalcating fluorphore 200 would be placed next to the single base mismatch site 206 (Fig. 14A) .
- the intercalcating type fluorescent label could be, for example, ethidium bromide or aeridine, or any other known fluorescent labels consistent with the objects of this device and its use.
- Fig. 14B and 15B show the condition of the reporter probe 202, the target DNA 204 and the mismatch base site 206 after the application of a pulse at the fluorescent perturbation value via the pad 210.
- the change from intercalated to the non-intercalated environment would produce a major change in fluorescent signal intensity of the label .
- the use of a mis-match site directed fluorophor label does not require that the hybrid be completely denatured during the process.
- an analysis procedure is preferred in which an appropriate pulsed "Fp" power level is applied which causes a mis-matched hybridization site to partially de-nature and re-nature relative to a matched hybridization site.
- Figs. 14C and 15C shows the relative fluorescent intensity as a function of varied applied power.
- This procedure provides a highly specific and discriminating method for single base mis ⁇ match analysis. Additional advantages include: (1) Longer probes (> 20-mer) than those used in conventional hybridization procedures can be used in this process, (2) Probe specificity is more determined by placement of the fluorescent label (particularly for single base mis ⁇ matches) , and (3) as the procedure does not require complete denaturation of the hybrid structures, each sample can be analyzed repetitively for providing a higher statistical significant data, such as through standard averaging techniques.
- the electronic stringency device disclosed herein may be advantageously used for DNA fingerprinting and analysis.
- An electronically addressable array measures DNA fragment sizes by determining the different electronic force necessary to dehybrize the fragment of varying lengths from capture probe sequences.
- three test sites 210 are shown labelled test sites A, B and C. This number of test sites may be greatly increased in an actual device, but three are shown for demonstration of the principle and technique.
- Capture probes 212 would be attached to the test sites 210 through the techniques described above. Fragments of a given, though likely unknown, first length 214 would be hybridized with the capture probe 212 at test site C 210.
- a second fragment 216 having presumably a different length than fragment 214 is hybridized to capture probe 212 at test site B 210.
- a fragment 218 having a presumably different length than fragments 214, 216 is hybridized to capture probe 212 at test site A 210.
- the test sites 210 are then subject to reverse potential at increasing current levels.
- the fluorescence from the test sites 210 is monitored.
- indications of dehybridization are detected, such as by observing the peak as described in connection with Figs. 12A, 12B, 13A and 13B, or by complete dehybridization.
- the complete dehybridization of the fragments 214, 216 and 218 are detected from the capture probes 212. Since the varying length fragments 214, 216 and 218 have different lengths, they will have different amounts of net charge.
- FIG. 16B shows the condition in which the test site C 210 has reached or exceed a reverse potential which caused the dehybridization of the fragment 214 from the capture probe 212.
- Fig. 16C when the reverse potential at test site 210 reaches that level at which the fragment 216 is subject to sufficient force to dehybridize from capture sequence 212, the fragment 216 separates from test site B 210. Finally, as the reverse potential is increased even further, the shortest fragment 218 is removed from the capture sequence 212 at test site A 210. In this way, the electric potential or current required to resolve different sized fragments from each test site is determined and correlated with the fragment size.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR9610618A BR9610618A (en) | 1995-09-27 | 1996-09-06 | Apparatus and methods for active programmable matrix devices |
NZ318253A NZ318253A (en) | 1995-09-27 | 1996-09-06 | Apparatus and methods for active programmable matrix devices |
JP51345297A JPH11512605A (en) | 1995-09-27 | 1996-09-06 | Apparatus and method for active programmable matrix device |
AU69689/96A AU723134B2 (en) | 1995-09-27 | 1996-09-06 | Methods for hybridization analysis utilizing electrically controlled hybridization |
EP96930748A EP0852617A4 (en) | 1995-09-27 | 1996-09-06 | Apparatus and methods for active programmable matrix devices |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/534,454 | 1995-09-27 | ||
US08/534,454 US5849486A (en) | 1993-11-01 | 1995-09-27 | Methods for hybridization analysis utilizing electrically controlled hybridization |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997012030A1 true WO1997012030A1 (en) | 1997-04-03 |
Family
ID=24130109
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/014353 WO1997012030A1 (en) | 1995-09-27 | 1996-09-06 | Apparatus and methods for active programmable matrix devices |
Country Status (9)
Country | Link |
---|---|
US (2) | US5849486A (en) |
EP (1) | EP0852617A4 (en) |
JP (1) | JPH11512605A (en) |
CN (1) | CN1202929A (en) |
AU (1) | AU723134B2 (en) |
BR (1) | BR9610618A (en) |
CA (1) | CA2233238A1 (en) |
NZ (1) | NZ318253A (en) |
WO (1) | WO1997012030A1 (en) |
Cited By (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2749393A1 (en) * | 1996-05-31 | 1997-12-05 | Motorola Inc | ELECTRODE CONFIGURATION FOR MATRIX ADDRESSING OF A MOLECULAR DETECTION DEVICE |
WO1998051819A1 (en) * | 1997-05-14 | 1998-11-19 | Nanogen, Inc. | Methods for electronic fluorescent perturbation for analysis and electronic perturbation catalysis for synthesis |
WO1999018434A1 (en) * | 1997-10-06 | 1999-04-15 | Trustees Of Tufts College | Self-encoding fiber optic sensor |
WO1999027351A1 (en) * | 1997-11-25 | 1999-06-03 | Lockheed Martin Energy Research Corporation | Bioluminescent bioreporter integrated circuit |
WO1999027140A1 (en) * | 1997-11-26 | 1999-06-03 | Lockheed Martin Energy Research Corporation | Integrated circuit biochip microsystem |
WO1999028500A1 (en) * | 1997-11-29 | 1999-06-10 | The Secretary Of State For Defence | Fluorimetric detection system of a nucleic acid |
EP0947819A2 (en) * | 1998-03-30 | 1999-10-06 | Hitachi Software Engineering Co., Ltd. | Sample application method and device |
WO2000012759A1 (en) * | 1998-08-26 | 2000-03-09 | Alpha Innotech Corporation | Biochip detection system |
EP0985142A2 (en) * | 1997-05-23 | 2000-03-15 | Lynx Therapeutics, Inc. | System and apparaus for sequential processing of analytes |
WO2000053311A1 (en) * | 1999-03-11 | 2000-09-14 | Combimatrix Corporation | Self assembling arrays |
EP1036085A1 (en) * | 1997-12-05 | 2000-09-20 | Nanogen, Inc. | Self-addressable self-assembling microelectronic integrated systems, component devices, mechanisms, methods, and procedures for molecular biological analysis and diagnostics |
WO2000058522A1 (en) * | 1999-03-30 | 2000-10-05 | Nanogen, Inc. | Single nucleotide polymorphic discrimination by electronic dot blot assay on semiconductor microchips |
WO2001042508A2 (en) * | 1999-12-09 | 2001-06-14 | Motorola, Inc. | Methods and compositions relating to electrical detection of nucleic acid reactions |
US6251595B1 (en) | 1998-06-18 | 2001-06-26 | Agilent Technologies, Inc. | Methods and devices for carrying out chemical reactions |
US6331274B1 (en) * | 1993-11-01 | 2001-12-18 | Nanogen, Inc. | Advanced active circuits and devices for molecular biological analysis and diagnostics |
JP2002522065A (en) * | 1998-08-10 | 2002-07-23 | ジェノミック ソリューションズ インコーポレイテッド | Heat and fluid circulation device for nucleic acid hybridization |
US6468742B2 (en) | 1993-11-01 | 2002-10-22 | Nanogen, Inc. | Methods for determination of single nucleic acid polymorphisms using bioelectronic microchip |
US6492122B2 (en) | 2000-11-09 | 2002-12-10 | Nanogen, Inc. | Quantitative analysis methods on active electronic microarrays |
US6518024B2 (en) | 1999-12-13 | 2003-02-11 | Motorola, Inc. | Electrochemical detection of single base extension |
WO2004011925A1 (en) * | 2002-07-31 | 2004-02-05 | Kabushiki Kaisha Toshiba | Base sequence detecting device and base sequence automatic analyzer |
US6703228B1 (en) | 1998-09-25 | 2004-03-09 | Massachusetts Institute Of Technology | Methods and products related to genotyping and DNA analysis |
JP2004271384A (en) * | 2003-03-10 | 2004-09-30 | Casio Comput Co Ltd | Dna analytical device and analytical method |
WO2004087303A1 (en) * | 2003-03-28 | 2004-10-14 | Fujitsu Limited | Target detecting device and target capturer, molecule adsorption/desorption device and molecule adsoprtion/desoption method, and protein detecting device and protein detecting method |
US6824669B1 (en) | 2000-02-17 | 2004-11-30 | Motorola, Inc. | Protein and peptide sensors using electrical detection methods |
WO2004081234A3 (en) * | 2003-03-10 | 2005-07-14 | Casio Computer Co Ltd | Dna analyzing apparatus, dna sensor, and analyzing method |
US7097974B1 (en) | 1998-08-28 | 2006-08-29 | Febit Biotech Gmbh | Support for a method for determining an analyte and a method for producing the support |
US7157050B2 (en) | 2002-09-06 | 2007-01-02 | Hitachi, Ltd. | System and method for detecting biological and chemical material |
US7348181B2 (en) | 1997-10-06 | 2008-03-25 | Trustees Of Tufts College | Self-encoding sensor with microspheres |
US7470540B2 (en) | 2000-10-17 | 2008-12-30 | Febit Ag | Method and device for the integrated synthesis and analysis of analytes on a support |
US7524672B2 (en) | 2004-09-22 | 2009-04-28 | Sandia Corporation | Microfluidic microarray systems and methods thereof |
US7655129B2 (en) | 1998-06-23 | 2010-02-02 | Osmetech Technology Inc. | Binding acceleration techniques for the detection of analytes |
US7700275B2 (en) | 2001-05-25 | 2010-04-20 | The Secretary Of State Of Defense | Detection system |
US7745203B2 (en) | 2002-07-31 | 2010-06-29 | Kabushiki Kaisha Toshiba | Base sequence detection apparatus and base sequence automatic analyzing apparatus |
US7887752B2 (en) | 2003-01-21 | 2011-02-15 | Illumina, Inc. | Chemical reaction monitor |
US7927546B2 (en) | 2005-10-07 | 2011-04-19 | Anagnostics Bioanalysis Gmbh | Device for the analysis of liquid samples |
USRE43097E1 (en) | 1994-10-13 | 2012-01-10 | Illumina, Inc. | Massively parallel signature sequencing by ligation of encoded adaptors |
US8426135B1 (en) | 2004-09-24 | 2013-04-23 | Sandia National Laboratories | High temperature flow-through device for rapid solubilization and analysis |
US8623597B2 (en) | 2002-05-21 | 2014-01-07 | Sony Corporation | Bioassay method, bioassay device, and bioassay substrate |
US9127308B2 (en) | 2002-03-07 | 2015-09-08 | Atlas Genetics Limited | Nucleic acid probes, their synthesis and use |
US9399795B2 (en) | 1998-06-24 | 2016-07-26 | Illumina, Inc. | Multiplex decoding of array sensors with microspheres |
US11193922B2 (en) | 2016-10-26 | 2021-12-07 | Roche Sequencing Solutions, Inc. | Multi-chip packaging of integrated circuits and flow cells for nanopore sequencing |
Families Citing this family (287)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6197508B1 (en) | 1990-09-12 | 2001-03-06 | Affymetrix, Inc. | Electrochemical denaturation and annealing of nucleic acid |
US7040653B1 (en) * | 2004-10-27 | 2006-05-09 | Automotive Technologies International, Inc. | Steering wheel assemblies for vehicles |
US6017696A (en) | 1993-11-01 | 2000-01-25 | Nanogen, Inc. | Methods for electronic stringency control for molecular biological analysis and diagnostics |
US6569382B1 (en) * | 1991-11-07 | 2003-05-27 | Nanogen, Inc. | Methods apparatus for the electronic, homogeneous assembly and fabrication of devices |
US6652808B1 (en) * | 1991-11-07 | 2003-11-25 | Nanotronics, Inc. | Methods for the electronic assembly and fabrication of devices |
US5605662A (en) | 1993-11-01 | 1997-02-25 | Nanogen, Inc. | Active programmable electronic devices for molecular biological analysis and diagnostics |
US5849486A (en) * | 1993-11-01 | 1998-12-15 | Nanogen, Inc. | Methods for hybridization analysis utilizing electrically controlled hybridization |
US6315953B1 (en) * | 1993-11-01 | 2001-11-13 | Nanogen, Inc. | Devices for molecular biological analysis and diagnostics including waveguides |
US6225059B1 (en) | 1993-11-01 | 2001-05-01 | Nanogen, Inc. | Advanced active electronic devices including collection electrodes for molecular biological analysis and diagnostics |
US6129828A (en) | 1996-09-06 | 2000-10-10 | Nanogen, Inc. | Apparatus and methods for active biological sample preparation |
US6068818A (en) * | 1993-11-01 | 2000-05-30 | Nanogen, Inc. | Multicomponent devices for molecular biological analysis and diagnostics |
US7101661B1 (en) | 1993-11-01 | 2006-09-05 | Nanogen, Inc. | Apparatus for active programmable matrix devices |
US5965452A (en) * | 1996-07-09 | 1999-10-12 | Nanogen, Inc. | Multiplexed active biologic array |
US6309602B1 (en) | 1993-11-01 | 2001-10-30 | Nanogen, Inc. | Stacked, reconfigurable system for electrophoretic transport of charged materials |
US7314708B1 (en) | 1998-08-04 | 2008-01-01 | Nanogen, Inc. | Method and apparatus for electronic synthesis of molecular structures |
US6306348B1 (en) * | 1993-11-01 | 2001-10-23 | Nanogen, Inc. | Inorganic permeation layer for micro-electric device |
US6254827B1 (en) | 1993-11-01 | 2001-07-03 | Nanogen, Inc. | Methods for fabricating multi-component devices for molecular biological analysis and diagnostics |
US7172864B1 (en) * | 1993-11-01 | 2007-02-06 | Nanogen | Methods for electronically-controlled enzymatic reactions |
US7582421B2 (en) * | 1993-11-01 | 2009-09-01 | Nanogen, Inc. | Methods for determination of single nucleic acid polymorphisms using a bioelectronic microchip |
US6207373B1 (en) | 1998-02-25 | 2001-03-27 | Nanogen, Inc. | Methods for determining nature of repeat units in DNA |
US6071699A (en) | 1996-06-07 | 2000-06-06 | California Institute Of Technology | Nucleic acid mediated electron transfer |
US5824473A (en) * | 1993-12-10 | 1998-10-20 | California Institute Of Technology | Nucleic acid mediated electron transfer |
DE69507289T2 (en) | 1994-03-15 | 1999-07-08 | Scient Generics Ltd | ELECTROCHEMICAL DENATUSING OF DOUBLE-STRANDED NUCLEIC ACID |
US6071394A (en) * | 1996-09-06 | 2000-06-06 | Nanogen, Inc. | Channel-less separation of bioparticles on a bioelectronic chip by dielectrophoresis |
US7857957B2 (en) | 1994-07-07 | 2010-12-28 | Gamida For Life B.V. | Integrated portable biological detection system |
US6403367B1 (en) | 1994-07-07 | 2002-06-11 | Nanogen, Inc. | Integrated portable biological detection system |
US5620850A (en) | 1994-09-26 | 1997-04-15 | President And Fellows Of Harvard College | Molecular recognition at surfaces derivatized with self-assembled monolayers |
US6140045A (en) * | 1995-03-10 | 2000-10-31 | Meso Scale Technologies | Multi-array, multi-specific electrochemiluminescence testing |
US6048734A (en) | 1995-09-15 | 2000-04-11 | The Regents Of The University Of Michigan | Thermal microvalves in a fluid flow method |
US20040086917A1 (en) * | 1995-09-27 | 2004-05-06 | Nanogen, Inc. | Methods for electronic fluorescent perturbation for analysis and electronic perturbation catalysis for synthesis |
DE69737883T2 (en) | 1996-04-25 | 2008-03-06 | Bioarray Solutions Ltd. | LIGHT-REGULATED, ELECTROKINETIC COMPOSITION OF PARTICLES TO SURFACES |
US6355436B1 (en) * | 1996-05-17 | 2002-03-12 | L'ecole Centrale De Lyon | Method for analyzing biological substances in a conductive liquid medium |
US7169556B2 (en) * | 1996-07-29 | 2007-01-30 | Nanosphere, Inc. | Nanoparticles having oligonucleotides attached thereto and uses therefor |
US7014992B1 (en) * | 1996-11-05 | 2006-03-21 | Clinical Micro Sensors, Inc. | Conductive oligomers attached to electrodes and nucleoside analogs |
US7160678B1 (en) | 1996-11-05 | 2007-01-09 | Clinical Micro Sensors, Inc. | Compositions for the electronic detection of analytes utilizing monolayers |
US7045285B1 (en) | 1996-11-05 | 2006-05-16 | Clinical Micro Sensors, Inc. | Electronic transfer moieties attached to peptide nucleic acids |
US7393645B2 (en) * | 1996-11-05 | 2008-07-01 | Clinical Micro Sensors, Inc. | Compositions for the electronic detection of analytes utilizing monolayers |
US7381525B1 (en) | 1997-03-07 | 2008-06-03 | Clinical Micro Sensors, Inc. | AC/DC voltage apparatus for detection of nucleic acids |
EP0938674B1 (en) * | 1996-11-16 | 2005-06-01 | NMI Naturwissenschaftliches und Medizinisches Institut an der Universität Tübingen in Reutlingen Stiftung Bürgerlichen Rechts | Array of microelements, method of contacting cells in a liquid environment and method for the production of an array of microelements |
US6706473B1 (en) | 1996-12-06 | 2004-03-16 | Nanogen, Inc. | Systems and devices for photoelectrophoretic transport and hybridization of oligonucleotides |
JP3795533B2 (en) * | 1996-12-12 | 2006-07-12 | プロルーム・リミテツド | Method and apparatus for detecting and identifying infectious substances |
DE19741715A1 (en) * | 1997-09-22 | 1999-03-25 | Hoechst Ag | New pentopyranosyl nucleoside compounds |
US6030781A (en) * | 1997-10-23 | 2000-02-29 | Motorola, Inc. | Electric field amplified oligonucleotide ligase analysis |
US6203758B1 (en) * | 1997-11-10 | 2001-03-20 | Bio-Pixel Ltd. | Micro-circuit system with array of functionalized micro-electrodes |
US7267948B2 (en) * | 1997-11-26 | 2007-09-11 | Ut-Battelle, Llc | SERS diagnostic platforms, methods and systems microarrays, biosensors and biochips |
US7090804B2 (en) | 1998-01-27 | 2006-08-15 | Clinical Mirco Sensors, Inc. | Amplification of nucleic acids with electronic detection |
US6287776B1 (en) | 1998-02-02 | 2001-09-11 | Signature Bioscience, Inc. | Method for detecting and classifying nucleic acid hybridization |
WO1999057314A1 (en) * | 1998-05-04 | 1999-11-11 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Electrical integrated nucleic acid isolation, purification and detection |
US6600026B1 (en) | 1998-05-06 | 2003-07-29 | Clinical Micro Sensors, Inc. | Electronic methods for the detection of analytes utilizing monolayers |
US20030153023A1 (en) * | 1999-05-13 | 2003-08-14 | Starzl Timothy W. | Enumeration method of analyte detection |
KR20010072846A (en) * | 1998-08-21 | 2001-07-31 | 추후제출 | Assays using crosslinkable immobilized nucleic acids |
US6740518B1 (en) | 1998-09-17 | 2004-05-25 | Clinical Micro Sensors, Inc. | Signal detection techniques for the detection of analytes |
US7135283B1 (en) | 1998-11-17 | 2006-11-14 | Nanogen, Inc. | Topoisomerase type II gene polymorphisms and their use in identifying drug resistance and pathogenic strains of microorganisms |
WO2000034521A1 (en) | 1998-12-08 | 2000-06-15 | Boston Probes, Inc. | Methods, kits and compositions for the identification of nucleic acids electrostatically bound to matrices |
JP3442327B2 (en) | 1998-12-15 | 2003-09-02 | 日立ソフトウエアエンジニアリング株式会社 | Hybridization detection method and biochip |
US20030032029A1 (en) * | 1998-12-21 | 2003-02-13 | Nanogen, Inc. | Three dimensional apparatus and method for integrating sample preparation and multiplex assays |
US6833267B1 (en) | 1998-12-30 | 2004-12-21 | Clinical Micro Sensors, Inc. | Tissue collection devices containing biosensors |
US6294063B1 (en) * | 1999-02-12 | 2001-09-25 | Board Of Regents, The University Of Texas System | Method and apparatus for programmable fluidic processing |
US6215894B1 (en) * | 1999-02-26 | 2001-04-10 | General Scanning, Incorporated | Automatic imaging and analysis of microarray biochips |
CN1185492C (en) | 1999-03-15 | 2005-01-19 | 清华大学 | Single-point strobed micro electromagnetic units array chip or electromagnetic biologic chip and application thereof |
TW496775B (en) | 1999-03-15 | 2002-08-01 | Aviva Bioscience Corp | Individually addressable micro-electromagnetic unit array chips |
US6403317B1 (en) * | 1999-03-26 | 2002-06-11 | Affymetrix, Inc. | Electronic detection of hybridization on nucleic acid arrays |
US6326173B1 (en) * | 1999-04-12 | 2001-12-04 | Nanogen/Becton Dickinson Partnership | Electronically mediated nucleic acid amplification in NASBA |
US6238868B1 (en) * | 1999-04-12 | 2001-05-29 | Nanogen/Becton Dickinson Partnership | Multiplex amplification and separation of nucleic acid sequences using ligation-dependant strand displacement amplification and bioelectronic chip technology |
EP1177423A4 (en) * | 1999-04-12 | 2004-10-27 | Nanogen Becton Dickinson Partn | Amplification and separation of nucleic acid sequences using strand displacement amplification and bioelectronic microchip technology |
WO2000061805A1 (en) * | 1999-04-12 | 2000-10-19 | Nanogen, Inc. | Methods for determination of single nucleic acid polymorphisms using a bioelectronic microchip |
US6235479B1 (en) * | 1999-04-13 | 2001-05-22 | Bio Merieux, Inc. | Methods and devices for performing analysis of a nucleic acid sample |
US20020177135A1 (en) | 1999-07-27 | 2002-11-28 | Doung Hau H. | Devices and methods for biochip multiplexing |
US6942771B1 (en) * | 1999-04-21 | 2005-09-13 | Clinical Micro Sensors, Inc. | Microfluidic systems in the electrochemical detection of target analytes |
US20040053290A1 (en) * | 2000-01-11 | 2004-03-18 | Terbrueggen Robert Henry | Devices and methods for biochip multiplexing |
DE19923966C2 (en) * | 1999-05-25 | 2003-04-24 | Phylos Inc | Detection system for the separation of sample components, its production and use |
WO2000073764A2 (en) | 1999-06-01 | 2000-12-07 | Baylor College Of Medicine | Composition and methods for the therapeutic use of an atonal-associated sequence |
US6811668B1 (en) * | 1999-06-22 | 2004-11-02 | Caliper Life Sciences, Inc. | Apparatus for the operation of a microfluidic device |
EP1360992A3 (en) * | 1999-06-22 | 2004-05-19 | Caliper Life Sciences, Inc. | Apparatus for the operation of a microfluidic device |
US20020119448A1 (en) * | 1999-06-23 | 2002-08-29 | Joseph A. Sorge | Methods of enriching for and identifying polymorphisms |
EP1218541B1 (en) | 1999-07-26 | 2008-12-10 | Clinical Micro Sensors, Inc. | Sequence determination of nucleic acids using electronic detection |
AU7730500A (en) | 1999-09-30 | 2001-04-30 | Nanogen, Inc. | Biomolecular attachment sites on microelectronic arrays and methods thereof |
JP2001186881A (en) * | 1999-10-22 | 2001-07-10 | Ngk Insulators Ltd | Method for producing dna chip |
US7115423B1 (en) | 1999-10-22 | 2006-10-03 | Agilent Technologies, Inc. | Fluidic structures within an array package |
CA2389769A1 (en) * | 1999-11-02 | 2001-05-10 | Celine Hu | Molecular microarrays and methods for production and use thereof |
US6875619B2 (en) | 1999-11-12 | 2005-04-05 | Motorola, Inc. | Microfluidic devices comprising biochannels |
US6361958B1 (en) | 1999-11-12 | 2002-03-26 | Motorola, Inc. | Biochannel assay for hybridization with biomaterial |
US6303082B1 (en) * | 1999-12-15 | 2001-10-16 | Nanogen, Inc. | Permeation layer attachment chemistry and method |
US6265170B1 (en) * | 2000-01-24 | 2001-07-24 | Ingeneus Corporation | Homogenous assay of duplex of triplex hybridization by means of multiple measurements under varied conditions |
CA2302827A1 (en) * | 2000-04-12 | 2001-10-12 | Michelle Furtado | Oligonucleotide and dna de-hybridization on surfaces |
US7001792B2 (en) * | 2000-04-24 | 2006-02-21 | Eagle Research & Development, Llc | Ultra-fast nucleic acid sequencing device and a method for making and using the same |
US6413792B1 (en) | 2000-04-24 | 2002-07-02 | Eagle Research Development, Llc | Ultra-fast nucleic acid sequencing device and a method for making and using the same |
US8232582B2 (en) | 2000-04-24 | 2012-07-31 | Life Technologies Corporation | Ultra-fast nucleic acid sequencing device and a method for making and using the same |
CA2407973C (en) * | 2000-05-03 | 2011-06-07 | Jen-Jr Gau | Biological identification system with integrated sensor chip |
US6912469B1 (en) * | 2000-05-05 | 2005-06-28 | Kenneth J. Cool | Electronic hybridization assay and sequence analysis |
US6602400B1 (en) | 2000-06-15 | 2003-08-05 | Motorola, Inc. | Method for enhanced bio-conjugation events |
EP1311839B1 (en) | 2000-06-21 | 2006-03-01 | Bioarray Solutions Ltd | Multianalyte molecular analysis using application-specific random particle arrays |
US9709559B2 (en) | 2000-06-21 | 2017-07-18 | Bioarray Solutions, Ltd. | Multianalyte molecular analysis using application-specific random particle arrays |
WO2002000842A2 (en) | 2000-06-23 | 2002-01-03 | The University Of Chicago | Methods for isolating centromere dna |
AU7333701A (en) | 2000-07-10 | 2002-01-21 | Univ Texas | Chromosome 3p21.3 genes are tumor suppressors |
US7501284B2 (en) * | 2000-07-31 | 2009-03-10 | Applera Corporation | Apparatus and method for specific release of captured extension products |
DE10038237A1 (en) * | 2000-08-04 | 2002-02-14 | Aventis Res & Tech Gmbh & Co | Procedure for the detection of mutations in nucleotide sequences |
JP2004525607A (en) * | 2000-08-11 | 2004-08-26 | ナノスフェアー インコーポレイテッド | Oligonucleotide-attached nanoparticles and methods of use |
AU2001284681A1 (en) * | 2000-09-11 | 2002-03-26 | The Government Of The United States Of America, As Represented By The Secretary Of The Navy | Fluidics system |
US6780584B1 (en) * | 2000-09-27 | 2004-08-24 | Nanogen, Inc. | Electronic systems and component devices for macroscopic and microscopic molecular biological reactions, analyses and diagnostics |
WO2002043828A2 (en) * | 2000-11-28 | 2002-06-06 | Nanogen, Inc. | Microtiter plate format device and methods for separating differently charged molecules using an electric field |
US7776571B2 (en) * | 2000-12-12 | 2010-08-17 | Autogenomics, Inc. | Multi-substrate biochip unit |
WO2002052045A1 (en) * | 2000-12-26 | 2002-07-04 | Aviva Biosciences | Active and biocompatible platforms prepared by polymerization of surface coating films |
WO2002054450A2 (en) * | 2001-01-04 | 2002-07-11 | Eagle Research & Development, Llc | Method of patterning a mask on the surface of a substrate and product manufactured thereby |
CN1302285C (en) * | 2001-01-12 | 2007-02-28 | 东丽株式会社 | Selectively hybridizable substance immobilization fiber, fiber array comprising bundle of such fibers, selective hybridizing method, device therefor and base |
US6692700B2 (en) | 2001-02-14 | 2004-02-17 | Handylab, Inc. | Heat-reduction methods and systems related to microfluidic devices |
US6575188B2 (en) | 2001-07-26 | 2003-06-10 | Handylab, Inc. | Methods and systems for fluid control in microfluidic devices |
US7829025B2 (en) | 2001-03-28 | 2010-11-09 | Venture Lending & Leasing Iv, Inc. | Systems and methods for thermal actuation of microfluidic devices |
US7192557B2 (en) | 2001-03-28 | 2007-03-20 | Handylab, Inc. | Methods and systems for releasing intracellular material from cells within microfluidic samples of fluids |
US7323140B2 (en) | 2001-03-28 | 2008-01-29 | Handylab, Inc. | Moving microdroplets in a microfluidic device |
US8895311B1 (en) | 2001-03-28 | 2014-11-25 | Handylab, Inc. | Methods and systems for control of general purpose microfluidic devices |
US6852287B2 (en) | 2001-09-12 | 2005-02-08 | Handylab, Inc. | Microfluidic devices having a reduced number of input and output connections |
US7010391B2 (en) | 2001-03-28 | 2006-03-07 | Handylab, Inc. | Methods and systems for control of microfluidic devices |
US7270786B2 (en) | 2001-03-28 | 2007-09-18 | Handylab, Inc. | Methods and systems for processing microfluidic samples of particle containing fluids |
US20020160427A1 (en) * | 2001-04-27 | 2002-10-31 | Febit Ag | Methods and apparatuses for electronic determination of analytes |
US6824974B2 (en) * | 2001-06-11 | 2004-11-30 | Genorx, Inc. | Electronic detection of biological molecules using thin layers |
US20040048241A1 (en) * | 2001-06-11 | 2004-03-11 | Freeman Beverly Annette | Methods for attaching molecules |
US7262063B2 (en) | 2001-06-21 | 2007-08-28 | Bio Array Solutions, Ltd. | Directed assembly of functional heterostructures |
CA2764307C (en) * | 2001-06-29 | 2015-03-03 | Meso Scale Technologies, Llc. | Assay plates, reader systems and methods for luminescence test measurements |
US6893822B2 (en) | 2001-07-19 | 2005-05-17 | Nanogen Recognomics Gmbh | Enzymatic modification of a nucleic acid-synthetic binding unit conjugate |
WO2003014732A1 (en) * | 2001-08-10 | 2003-02-20 | Symyx Technologies, Inc. | Apparatuses and methods for creating and testing pre-formulations and systems for same |
US20060073530A1 (en) * | 2001-08-15 | 2006-04-06 | Olaf Schneewind | Methods and compositions involving sortase B |
US6890409B2 (en) * | 2001-08-24 | 2005-05-10 | Applera Corporation | Bubble-free and pressure-generating electrodes for electrophoretic and electroosmotic devices |
US20020169730A1 (en) * | 2001-08-29 | 2002-11-14 | Emmanuel Lazaridis | Methods for classifying objects and identifying latent classes |
KR100449069B1 (en) * | 2001-09-12 | 2004-09-18 | 한국전자통신연구원 | Microelectrode, microelectrode array and a method for manufacturing the microelectrode |
EP1432829A4 (en) * | 2001-10-04 | 2005-01-19 | Univ California | Detection of polynucleotide hybridization |
ES2661167T3 (en) | 2001-10-15 | 2018-03-27 | Bioarray Solutions Ltd. | Multiplexed analysis of polymorphic loci by simultaneous consultation and enzyme-mediated detection |
US7244611B2 (en) | 2001-10-23 | 2007-07-17 | Nikon Research Corporation Of America | Methods and devices for hybridization and binding assays using thermophoresis |
US20060134683A1 (en) * | 2001-10-23 | 2006-06-22 | Michael Sogard | Methods and devices for hybridization and binding assays using thermophoresis |
US7075187B1 (en) * | 2001-11-09 | 2006-07-11 | Combimatrix Corporation | Coating material over electrodes to support organic synthesis |
WO2003046221A1 (en) * | 2001-11-26 | 2003-06-05 | Institut Molekulyarnoi Biologii Im.V.A.Engelgardta Rossiiskoi Akademii Nauk | Method for the specific identification of orthopoxvirus with the aid of a miniature biological chip. |
US6960298B2 (en) | 2001-12-10 | 2005-11-01 | Nanogen, Inc. | Mesoporous permeation layers for use on active electronic matrix devices |
US20070178477A1 (en) * | 2002-01-16 | 2007-08-02 | Nanomix, Inc. | Nanotube sensor devices for DNA detection |
US20060228723A1 (en) * | 2002-01-16 | 2006-10-12 | Keith Bradley | System and method for electronic sensing of biomolecules |
US20040115672A1 (en) * | 2002-02-01 | 2004-06-17 | Rastilav Levicky | Use of electrical fields to control interactions between proteins and nucleic acid constructions immobilized on solid supports |
DE10204566A1 (en) * | 2002-02-04 | 2003-08-14 | Nanogen Recognomics Gmbh | Method for determining the methylation pattern of DNA |
US6887362B2 (en) * | 2002-02-06 | 2005-05-03 | Nanogen, Inc. | Dielectrophoretic separation and immunoassay methods on active electronic matrix devices |
US20030152934A1 (en) * | 2002-02-11 | 2003-08-14 | Industrial Technology Research Institute | High performance nucleic acid hybridization device and process |
DE10210051B4 (en) * | 2002-03-07 | 2005-10-13 | Siemens Ag | Device for the electrochemical detection of a nucleotide sequence, analysis cassette for such a device and method for producing such an analysis cassette |
US7604981B1 (en) * | 2002-03-08 | 2009-10-20 | The Board Of Trustees Of The Leland Stanford Junior University | Excitable target marker detection |
US20030194709A1 (en) * | 2002-04-10 | 2003-10-16 | Xing Yang | Hydrophobic zone device |
US7687256B2 (en) * | 2002-04-11 | 2010-03-30 | Spire Corporation | Surface activated biochip |
US20060052320A1 (en) * | 2002-05-06 | 2006-03-09 | Limin Li | Mammalian genes involved in rapamycin resistance and tumorgenesis annexin XIII genes |
CA2484732A1 (en) * | 2002-05-07 | 2003-11-20 | The Research Foundation Of State University Of New York | A method to rapidly prepare and screen formulations and compositions containing same |
US6841379B2 (en) | 2002-05-15 | 2005-01-11 | Beckman Coulter, Inc. | Conductive microplate |
AU2003247288A1 (en) * | 2002-05-24 | 2003-12-12 | Fraunhofer-Gesellschaft Zur Forderung Der Angewandten Forschung E.V. | Method for the manipulation of molecules in a fluid using an electrical field |
AU2003238501A1 (en) * | 2002-06-14 | 2003-12-31 | Axaron Bioscience Ag | Hybridization chamber |
US20060003437A1 (en) * | 2002-06-26 | 2006-01-05 | Fujitsu Limited | Target detecting device and target capturer, device and method for molecular adsorption or desorption, and device and method for protein detection |
US20040011650A1 (en) * | 2002-07-22 | 2004-01-22 | Frederic Zenhausern | Method and apparatus for manipulating polarizable analytes via dielectrophoresis |
US7601493B2 (en) * | 2002-07-26 | 2009-10-13 | Nanogen, Inc. | Methods and apparatus for screening and detecting multiple genetic mutations |
US8020433B2 (en) * | 2003-03-25 | 2011-09-20 | Tearlab Research, Inc. | Systems and methods for a sample fluid collection device |
US7810380B2 (en) | 2003-03-25 | 2010-10-12 | Tearlab Research, Inc. | Systems and methods for collecting tear film and measuring tear film osmolarity |
EP1578396A4 (en) | 2002-08-12 | 2007-01-17 | David Kirn | Methods and compositions concerning poxviruses and cancer |
US7153687B2 (en) | 2002-08-13 | 2006-12-26 | Hong Kong Dna Chips Limited | Apparatus and methods for detecting DNA in biological samples |
WO2004020581A2 (en) * | 2002-08-15 | 2004-03-11 | Functional Genetics, Inc. | Mammalian genes involved in rapamycin resistance and tumorgenesis: rapr7 genes |
US20060099676A1 (en) * | 2002-08-15 | 2006-05-11 | Limin Li | Mammalian genes involved in rapamycin resistance and tumorgenesis: rapr6 genes |
US7267751B2 (en) * | 2002-08-20 | 2007-09-11 | Nanogen, Inc. | Programmable multiplexed active biologic array |
JP4031322B2 (en) * | 2002-08-26 | 2008-01-09 | 独立行政法人科学技術振興機構 | Droplet operation device |
US7157228B2 (en) * | 2002-09-09 | 2007-01-02 | Bioarray Solutions Ltd. | Genetic analysis and authentication |
WO2004024949A2 (en) * | 2002-09-13 | 2004-03-25 | Hvidovre Hospital | Method of rapid detection of mutations and nucleotide polymorphisms using chemometrics |
US7595883B1 (en) | 2002-09-16 | 2009-09-29 | The Board Of Trustees Of The Leland Stanford Junior University | Biological analysis arrangement and approach therefor |
US7960184B2 (en) * | 2002-09-20 | 2011-06-14 | George Mason Intellectual Properties, Inc. | Methods and devices for active bioassay |
US7329545B2 (en) | 2002-09-24 | 2008-02-12 | Duke University | Methods for sampling a liquid flow |
US6911132B2 (en) | 2002-09-24 | 2005-06-28 | Duke University | Apparatus for manipulating droplets by electrowetting-based techniques |
US20050009051A1 (en) * | 2002-09-27 | 2005-01-13 | Board Of Regents, The University Of Texas | Diagnosis of mould infection |
WO2004033614A1 (en) * | 2002-10-10 | 2004-04-22 | Fujitsu Limited | Molecule-releasing apparatus and molecule-releasing method |
US7932098B2 (en) * | 2002-10-31 | 2011-04-26 | Hewlett-Packard Development Company, L.P. | Microfluidic system utilizing thin-film layers to route fluid |
US20040086872A1 (en) * | 2002-10-31 | 2004-05-06 | Childers Winthrop D. | Microfluidic system for analysis of nucleic acids |
AU2003298655A1 (en) | 2002-11-15 | 2004-06-15 | Bioarray Solutions, Ltd. | Analysis, secure access to, and transmission of array images |
CA2508359A1 (en) * | 2002-12-12 | 2004-06-24 | Nanosphere, Inc. | Direct snp detection with unamplified dna |
US20040166520A1 (en) * | 2003-01-03 | 2004-08-26 | Connolly D. Michael | Identifying items with nucleic acid taggants |
US7282130B2 (en) | 2003-01-31 | 2007-10-16 | Agilent Technologies, Inc. | Apparatus and method for control of biopolymer translocation through a nanopore |
DE10309201A1 (en) * | 2003-02-25 | 2004-09-16 | Siemens Ag | Sample carrier, for reactor, to take sample oligonucleotides as interactive partners for identification of DNA sequences, has inserts pushed through passage openings to lower electrical contacts |
US20050009066A1 (en) * | 2003-05-15 | 2005-01-13 | Connolly Dennis M. | Methods for localizing target molecules in a flowing fluid sample |
US7341841B2 (en) | 2003-07-12 | 2008-03-11 | Accelr8 Technology Corporation | Rapid microbial detection and antimicrobial susceptibility testing |
AU2004273783A1 (en) | 2003-07-12 | 2005-03-31 | Accelr8 Technology Corporation | Sensitive and rapid biodetection |
US20120077206A1 (en) | 2003-07-12 | 2012-03-29 | Accelr8 Technology Corporation | Rapid Microbial Detection and Antimicrobial Susceptibility Testing |
EP1654066B1 (en) | 2003-07-31 | 2014-11-12 | Handylab, Inc. | Processing particle-containing samples |
WO2005029705A2 (en) | 2003-09-18 | 2005-03-31 | Bioarray Solutions, Ltd. | Number coding for identification of subtypes of coded types of solid phase carriers |
WO2005031305A2 (en) | 2003-09-22 | 2005-04-07 | Bioarray Solutions, Ltd. | Surface immobilized polyelectrolyte with multiple functional groups capable of covalently bonding to biomolecules |
JP4328168B2 (en) * | 2003-10-02 | 2009-09-09 | ソニー株式会社 | Detection unit for interaction between substances using capillary phenomenon, method using the detection unit, and substrate for bioassay |
WO2005040755A2 (en) * | 2003-10-20 | 2005-05-06 | The Regents Of The University Of California | Nanoscale transduction systems for detecting molecular interactions |
EP1692298A4 (en) | 2003-10-28 | 2008-08-13 | Bioarray Solutions Ltd | Optimization of gene expression analysis using immobilized capture probes |
CN1882703B (en) | 2003-10-29 | 2011-07-06 | 佰尔瑞溶液有限公司 | Multiplexed nucleic acid analysis by fragmentation of double-stranded DNA |
US7341834B2 (en) * | 2003-12-15 | 2008-03-11 | Geneohn Sciences, Inc. | Multiplexed electrochemical detection system and method |
WO2005093388A1 (en) * | 2004-03-26 | 2005-10-06 | Infectio Recherche Inc. | Removable microfluidic flow cell |
US8852862B2 (en) | 2004-05-03 | 2014-10-07 | Handylab, Inc. | Method for processing polynucleotide-containing samples |
US8470586B2 (en) | 2004-05-03 | 2013-06-25 | Handylab, Inc. | Processing polynucleotide-containing samples |
US20060008823A1 (en) * | 2004-05-12 | 2006-01-12 | Kemp Jennifer T | DNA profiling and SNP detection utilizing microarrays |
EP1765501A1 (en) | 2004-05-28 | 2007-03-28 | Board of Regents, The University of Texas System | Programmable fluidic processors |
CA2569202A1 (en) * | 2004-05-28 | 2005-12-15 | Board Of Regents, The University Of Texas System | Multigene predictors of response to chemotherapy |
US7848889B2 (en) | 2004-08-02 | 2010-12-07 | Bioarray Solutions, Ltd. | Automated analysis of multiplexed probe-target interaction patterns: pattern matching and allele identification |
EP1781771A2 (en) * | 2004-08-24 | 2007-05-09 | Nanomix, Inc. | Nanotube sensor devices for dna detection |
DE602005021525D1 (en) | 2004-09-14 | 2010-07-08 | Univ Colorado | R TREATMENT WITH BUCINDOLOL |
US7828954B2 (en) * | 2004-09-21 | 2010-11-09 | Gamida For Life B.V. | Electrode based patterning of thin film self-assembled nanoparticles |
US7314542B2 (en) * | 2004-09-23 | 2008-01-01 | Nanogen, Inc. | Methods and materials for optimization of electronic transportation and hybridization reactions |
WO2006065598A2 (en) * | 2004-12-13 | 2006-06-22 | Geneohm Sciences, Inc. | Fluidic cartridges for electrochemical detection of dna |
EP1859330B1 (en) | 2005-01-28 | 2012-07-04 | Duke University | Apparatuses and methods for manipulating droplets on a printed circuit board |
WO2006089268A2 (en) * | 2005-02-18 | 2006-08-24 | The University Of North Carolina At Chapel Hill | Gene and cognate protein profiles and methods to determine connective tissue markers in normal and pathologic conditions |
US7824927B2 (en) * | 2005-04-05 | 2010-11-02 | George Mason Intellectual Properties, Inc. | Analyte detection using an active assay |
US8486629B2 (en) | 2005-06-01 | 2013-07-16 | Bioarray Solutions, Ltd. | Creation of functionalized microparticle libraries by oligonucleotide ligation or elongation |
US20070037169A1 (en) * | 2005-08-09 | 2007-02-15 | Combimatrix Corporation | Selective Dehybridization using Electrochemically-Generated Reagent on an Electrode Microarray |
KR101772375B1 (en) | 2005-09-07 | 2017-08-29 | 신라젠(주) | Systemic treatment of metastatic and/or systemically-disseminated cancers using GM-CSF-expressing poxviruses |
US8980246B2 (en) | 2005-09-07 | 2015-03-17 | Sillajen Biotherapeutics, Inc. | Oncolytic vaccinia virus cancer therapy |
CA2643225A1 (en) * | 2006-02-28 | 2007-09-07 | Pfizer Products Inc. | Gene predictors of response to metastatic colorectal chemotherapy |
US10900066B2 (en) | 2006-03-24 | 2021-01-26 | Handylab, Inc. | Microfluidic system for amplifying and detecting polynucleotides in parallel |
DK2001990T3 (en) | 2006-03-24 | 2016-10-03 | Handylab Inc | Integrated microfluidic sample processing system and method for its use |
US11806718B2 (en) | 2006-03-24 | 2023-11-07 | Handylab, Inc. | Fluorescence detector for microfluidic diagnostic system |
US7998708B2 (en) * | 2006-03-24 | 2011-08-16 | Handylab, Inc. | Microfluidic system for amplifying and detecting polynucleotides in parallel |
US8088616B2 (en) | 2006-03-24 | 2012-01-03 | Handylab, Inc. | Heater unit for microfluidic diagnostic system |
US7856272B2 (en) * | 2006-04-28 | 2010-12-21 | Flint Hills Scientific, L.L.C. | Implantable interface for a medical device system |
US7687103B2 (en) * | 2006-08-31 | 2010-03-30 | Gamida For Life B.V. | Compositions and methods for preserving permeation layers for use on active electronic matrix devices |
ES2551892T3 (en) | 2006-09-15 | 2015-11-24 | Ottawa Health Research Institute | Oncolytic rhabdovirus |
WO2008060604A2 (en) | 2006-11-14 | 2008-05-22 | Handylab, Inc. | Microfluidic system for amplifying and detecting polynucleotides in parallel |
EP2091647A2 (en) | 2006-11-14 | 2009-08-26 | Handylab, Inc. | Microfluidic system for amplifying and detecting polynucleotides in parallel |
US20110092380A1 (en) * | 2006-12-29 | 2011-04-21 | Febit Holding Gmbh | Improved molecular-biological processing equipment |
US9618139B2 (en) | 2007-07-13 | 2017-04-11 | Handylab, Inc. | Integrated heater and magnetic separator |
US20090136385A1 (en) | 2007-07-13 | 2009-05-28 | Handylab, Inc. | Reagent Tube |
JP5651011B2 (en) | 2007-07-13 | 2015-01-07 | ハンディーラブ インコーポレイテッド | Polynucleotide capture material and method of use thereof |
USD621060S1 (en) | 2008-07-14 | 2010-08-03 | Handylab, Inc. | Microfluidic cartridge |
US8133671B2 (en) | 2007-07-13 | 2012-03-13 | Handylab, Inc. | Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples |
US8182763B2 (en) | 2007-07-13 | 2012-05-22 | Handylab, Inc. | Rack for sample tubes and reagent holders |
US8105783B2 (en) | 2007-07-13 | 2012-01-31 | Handylab, Inc. | Microfluidic cartridge |
US9186677B2 (en) | 2007-07-13 | 2015-11-17 | Handylab, Inc. | Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples |
US8287820B2 (en) | 2007-07-13 | 2012-10-16 | Handylab, Inc. | Automated pipetting apparatus having a combined liquid pump and pipette head system |
US8268246B2 (en) * | 2007-08-09 | 2012-09-18 | Advanced Liquid Logic Inc | PCB droplet actuator fabrication |
US7977660B2 (en) * | 2007-08-14 | 2011-07-12 | General Electric Company | Article, device, and method |
RU2010118611A (en) * | 2007-10-09 | 2011-11-20 | Юниверсити Оф Нотр Дам Дю Лак (Us) | MICROFLUID PLATFORMS FOR DETECTING MULTIPLE TARGETS |
US20090137925A1 (en) * | 2007-11-23 | 2009-05-28 | Divya Cantor | Impedance Spectroscopy Cervix Scanning Apparatus and Method |
GB0803593D0 (en) * | 2008-02-27 | 2008-04-02 | Univ Southampton | Method |
EP2257646A1 (en) * | 2008-02-29 | 2010-12-08 | ISIS Innovation Limited | Diagnostic methods |
US9817001B2 (en) | 2008-05-27 | 2017-11-14 | Boston Heart Diagnostics Corporation | Methods for determining LDL cholesterol treatment |
USD618820S1 (en) | 2008-07-11 | 2010-06-29 | Handylab, Inc. | Reagent holder |
USD787087S1 (en) | 2008-07-14 | 2017-05-16 | Handylab, Inc. | Housing |
US8470541B1 (en) | 2008-09-27 | 2013-06-25 | Boston Heart Diagnostics Corporation | Methods for separation and immuno-detection of biomolecules, and apparatus related thereto |
FI20095501A0 (en) * | 2009-05-04 | 2009-05-04 | Pekka Haenninen | Procedure for characterization and / or determination of samples |
US8665439B2 (en) * | 2009-06-30 | 2014-03-04 | Microbix Biosystems, Inc. | Method and apparatus for limiting effects of refraction in cytometry |
US8778279B2 (en) * | 2009-07-06 | 2014-07-15 | Sony Corporation | Microfluidic device |
CN102472709B (en) * | 2009-07-06 | 2015-07-15 | 索尼公司 | Microfluidic device having onboard tissue or cell sample handling capability |
CN103335945A (en) * | 2009-07-07 | 2013-10-02 | 索尼公司 | Microfluidic device |
WO2011005757A1 (en) * | 2009-07-07 | 2011-01-13 | Sony Corporation | Microfluidic device adapted for post-centrifugation use with selective sample extraction and methods for its use |
WO2011005754A1 (en) * | 2009-07-08 | 2011-01-13 | Sony Corporation | Microfluidic device having a flow channel within a gain medium |
US9409983B2 (en) | 2009-07-23 | 2016-08-09 | The Board Of Trustess Of The University Of Illinois | Methods and compositions involving PBEF inhibitors for lung inflammation conditions and diseases |
WO2011032088A1 (en) | 2009-09-11 | 2011-03-17 | Arca Biopharma, Inc. | Polymorphisms in the pde3a gene |
DK2477499T3 (en) | 2009-09-14 | 2018-06-06 | Sillajen Biotherapeutics Inc | COMBINATION CANCER THERAPY WITH ONCOLYTIC VACCINIA VIRUS |
CN101738417B (en) * | 2009-12-08 | 2012-09-05 | 清华大学 | Chip for detecting biochemical substances based on cold field electrons, and detection method |
JP6025255B2 (en) | 2009-12-10 | 2016-11-16 | ターンストーン リミテッド パートナーシップ | Oncolytic rhabdovirus |
DK2515899T3 (en) | 2009-12-23 | 2016-08-15 | Arca Biopharma Inc | METHODS AND COMPOSITIONS FOR CARDIOVASCULAR DISEASES AND CONDITIONS |
US8974651B2 (en) | 2010-04-17 | 2015-03-10 | C.C. Imex | Illuminator for visualization of fluorophores |
WO2012094386A1 (en) | 2011-01-04 | 2012-07-12 | Jennerex Inc. | Generation of antibodies to tumor antigens and generation of tumor specific complement dependent cytotoxicity by administration of oncolytic vaccinia virus |
WO2012094459A2 (en) | 2011-01-06 | 2012-07-12 | Glezer Eli N | Assay cartridges and methods of using the same |
BR112013020636A2 (en) | 2011-02-15 | 2017-09-05 | Microbix Biosystems Inc | METHODS, SYSTEMS AND DEVICES TO PERFORM FLOW CYTOMETRY |
EP2681566A2 (en) | 2011-02-28 | 2014-01-08 | University of Iowa Research Foundation | Anti-müllerian hormone changes in pregnancy and prediction ofadverse pregnancy outcomes and gender |
EP2683831B1 (en) | 2011-03-07 | 2015-09-23 | Accelerate Diagnostics, Inc. | Rapid cell purification systems |
US10254204B2 (en) | 2011-03-07 | 2019-04-09 | Accelerate Diagnostics, Inc. | Membrane-assisted purification |
CA2829300A1 (en) | 2011-03-08 | 2012-09-13 | King Abdullah University Of Science And Technology | Molecular biomarker set for early detection of ovarian cancer |
RU2690374C2 (en) | 2011-04-15 | 2019-06-03 | Бектон, Дикинсон Энд Компани | Scanning in real time microfluid thermal cycler and methods of synchronized thermal cycling and scanning optical detection |
ES2627529T3 (en) | 2011-06-08 | 2017-07-28 | Children's Hospital Of Eastern Ontario Research Institute Inc. | Compositions for glioblastoma treatment |
WO2013036799A2 (en) | 2011-09-09 | 2013-03-14 | Fred Hutchinson Cancer Research Center | Methods and compositions involving nkg2d inhibitors and cancer |
CA2849917C (en) | 2011-09-30 | 2020-03-31 | Becton, Dickinson And Company | Unitized reagent strip |
USD692162S1 (en) | 2011-09-30 | 2013-10-22 | Becton, Dickinson And Company | Single piece reagent holder |
WO2013056087A2 (en) | 2011-10-13 | 2013-04-18 | Boston Heart Diagnostics | Compositions and methods for treating and preventing coronary heart disease |
EP2773892B1 (en) | 2011-11-04 | 2020-10-07 | Handylab, Inc. | Polynucleotide sample preparation device |
DE102011121195B4 (en) * | 2011-12-16 | 2013-08-29 | Max-Planck-Institut für marine Mikrobiologie | Sensor device for determining an oxygen content of a fluid, a method for manufacturing and a method for calibrating such a sensor device |
BR112014018995B1 (en) | 2012-02-03 | 2021-01-19 | Becton, Dickson And Company | systems to perform automated testing |
CA3040684C (en) * | 2012-08-20 | 2023-02-07 | Hod Finkelstein | Method and system for fluorescence lifetime based sequencing |
EP3919174A3 (en) | 2012-10-24 | 2022-03-09 | Genmark Diagnostics Inc. | Integrated multiplex target analysis |
US20140322706A1 (en) | 2012-10-24 | 2014-10-30 | Jon Faiz Kayyem | Integrated multipelx target analysis |
WO2014116721A1 (en) | 2013-01-22 | 2014-07-31 | The Arizona Board Of Regents For And On Behalf Of Arizona State University | Geminiviral vector for expression of rituximab |
WO2014127478A1 (en) | 2013-02-21 | 2014-08-28 | Children's Hospital Of Eastern Ontario Research Institute Inc. | Vaccine composition |
US9677109B2 (en) | 2013-03-15 | 2017-06-13 | Accelerate Diagnostics, Inc. | Rapid determination of microbial growth and antimicrobial susceptibility |
CN107866286A (en) | 2013-03-15 | 2018-04-03 | 金马克诊断股份有限公司 | For manipulating system, the method and apparatus of deformable fluid container |
US9828624B2 (en) | 2013-07-24 | 2017-11-28 | Boston Heart Diagnostics Corporation | Driving patient compliance with therapy |
US9498778B2 (en) | 2014-11-11 | 2016-11-22 | Genmark Diagnostics, Inc. | Instrument for processing cartridge for performing assays in a closed sample preparation and reaction system |
USD881409S1 (en) | 2013-10-24 | 2020-04-14 | Genmark Diagnostics, Inc. | Biochip cartridge |
US9835587B2 (en) | 2014-04-01 | 2017-12-05 | C.C. Imex | Electrophoresis running tank assembly |
ES2828278T3 (en) | 2014-09-23 | 2021-05-25 | Tearlab Res Inc | Microfluidic tear collection integration system and lateral flow analysis of analytes of interest |
US10005080B2 (en) | 2014-11-11 | 2018-06-26 | Genmark Diagnostics, Inc. | Instrument and cartridge for performing assays in a closed sample preparation and reaction system employing electrowetting fluid manipulation |
CA2968221A1 (en) | 2014-11-17 | 2016-05-26 | Boston Heart Diagnostic Corporation | Cardiovascular disease risk assessment |
EP3224362A4 (en) | 2014-11-26 | 2018-06-06 | The Regents of The University of California | Therapeutic compositions comprising transcription factors and methods of making and using the same |
US10253355B2 (en) | 2015-03-30 | 2019-04-09 | Accelerate Diagnostics, Inc. | Instrument and system for rapid microorganism identification and antimicrobial agent susceptibility testing |
US10023895B2 (en) | 2015-03-30 | 2018-07-17 | Accelerate Diagnostics, Inc. | Instrument and system for rapid microogranism identification and antimicrobial agent susceptibility testing |
US20180215322A1 (en) * | 2017-01-31 | 2018-08-02 | Yakima Products, Inc. | Rooftop cargo carrier system |
CA3117112A1 (en) | 2018-10-31 | 2020-05-07 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Biomarkers and methods of use for radiation-induced lung injury |
CN112014366B (en) * | 2020-08-11 | 2024-01-02 | 国联汽车动力电池研究院有限责任公司 | Method for identifying stability of positive electrode material |
DE102020128003A1 (en) * | 2020-10-23 | 2020-12-31 | Bmg Labtech Gmbh | Microplate reader |
CN116840526B (en) * | 2023-09-01 | 2023-10-31 | 江苏协和电子股份有限公司 | Needle head, PCB detection equipment using needle head and use method |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5252743A (en) * | 1989-11-13 | 1993-10-12 | Affymax Technologies N.V. | Spatially-addressable immobilization of anti-ligands on surfaces |
US5412087A (en) * | 1992-04-24 | 1995-05-02 | Affymax Technologies N.V. | Spatially-addressable immobilization of oligonucleotides and other biological polymers on surfaces |
US5434049A (en) * | 1992-02-28 | 1995-07-18 | Hitachi, Ltd. | Separation of polynucleotides using supports having a plurality of electrode-containing cells |
Family Cites Families (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5036087A (en) * | 1973-07-13 | 1975-04-04 | ||
US3995190A (en) * | 1974-09-19 | 1976-11-30 | Butler, Binion, Rice, Cook & Knapp | Mobile ion film memory |
US4283773A (en) | 1977-08-30 | 1981-08-11 | Xerox Corporation | Programmable master controller communicating with plural controllers |
IE53020B1 (en) * | 1981-08-05 | 1988-05-11 | Ici Plc | Reflected light measuring apparatus |
FI63596C (en) * | 1981-10-16 | 1983-07-11 | Orion Yhtymae Oy | MICROBIA DIAGNOSIS FOERFARANDE SOM GRUNDAR SIG PAO SKIKTSHYBRIDISERING AV NUCLEINSYROR OCH VID FOERFARANDET ANVAENDA KOMBINATIONER AV REAGENSER |
US4580895A (en) * | 1983-10-28 | 1986-04-08 | Dynatech Laboratories, Incorporated | Sample-scanning photometer |
GB2150696B (en) | 1983-11-25 | 1988-09-01 | Mars Inc | Automatic test equipment |
FI71768C (en) * | 1984-02-17 | 1987-02-09 | Orion Yhtymae Oy | Enhanced nucleic acid reagents and process for their preparation. |
US4828979A (en) * | 1984-11-08 | 1989-05-09 | Life Technologies, Inc. | Nucleotide analogs for nucleic acid labeling and detection |
US4584075A (en) * | 1984-11-26 | 1986-04-22 | Ionics Incorporated | Process and apparatus for electrically desorbing components selectively sorbed on an electrolytically conducting barrier |
GB8432118D0 (en) * | 1984-12-19 | 1985-01-30 | Malcolm A D B | Sandwich hybridisation technique |
US4594135A (en) * | 1985-02-20 | 1986-06-10 | Ionics Incorporated | Process and apparatus for electrically desorbing components selectively sorbed on granules |
US5096807A (en) * | 1985-03-06 | 1992-03-17 | Murex Corporation | Imaging immunoassay detection system with background compensation and its use |
US4751177A (en) * | 1985-06-13 | 1988-06-14 | Amgen | Methods and kits for performing nucleic acid hybridization assays |
US4816418A (en) * | 1985-07-22 | 1989-03-28 | Sequoia-Turner Corporation | Method and apparatus for performing automated, multi-sequential immunoassays |
EP0213825A3 (en) * | 1985-08-22 | 1989-04-26 | Molecular Devices Corporation | Multiple chemically modulated capacitance |
US4822566A (en) * | 1985-11-19 | 1989-04-18 | The Johns Hopkins University | Optimized capacitive sensor for chemical analysis and measurement |
EP0228075B1 (en) * | 1986-01-03 | 1991-04-03 | Molecular Diagnostics, Inc. | Eucaryotic genomic dna dot-blot hybridization method |
US5242797A (en) * | 1986-03-21 | 1993-09-07 | Myron J. Block | Nucleic acid assay method |
US5125748A (en) * | 1986-03-26 | 1992-06-30 | Beckman Instruments, Inc. | Optical detection module for use in an automated laboratory work station |
ATE111083T1 (en) | 1986-10-22 | 1994-09-15 | Abbott Lab | CHEMILUMINESCENT ACRIDINIUM AND PHENANTRIDINIUM SALTS. |
US5202231A (en) * | 1987-04-01 | 1993-04-13 | Drmanac Radoje T | Method of sequencing of genomes by hybridization of oligonucleotide probes |
YU57087A (en) | 1987-04-01 | 1990-08-31 | Centar Za Genticko Inzenjerstv | Process for obtaining genome by hebridization and oligonucleotidic tests |
US5114674A (en) * | 1987-05-01 | 1992-05-19 | Biotronic Systems Corporation | Added array of molecular chains for interfering with electrical fields |
US4787963A (en) * | 1987-05-04 | 1988-11-29 | Syntro Corporation | Method and means for annealing complementary nucleic acid molecules at an accelerated rate |
US5074977A (en) | 1987-05-05 | 1991-12-24 | The Washington Technology Center | Digital biosensors and method of using same |
US5436170A (en) * | 1987-07-27 | 1995-07-25 | Commonwealth Scientific And Industrial Research Organization | Receptor membranes |
GB8810400D0 (en) * | 1988-05-03 | 1988-06-08 | Southern E | Analysing polynucleotide sequences |
US4828729A (en) | 1988-04-13 | 1989-05-09 | The United States Of America As Represented By The Secretary Of The Air Force | Molybdenum disulfide - molybdenum oxide lubricants |
US4908112A (en) * | 1988-06-16 | 1990-03-13 | E. I. Du Pont De Nemours & Co. | Silicon semiconductor wafer for analyzing micronic biological samples |
US5188963A (en) | 1989-11-17 | 1993-02-23 | Gene Tec Corporation | Device for processing biological specimens for analysis of nucleic acids |
US5075077A (en) * | 1988-08-02 | 1991-12-24 | Abbott Laboratories | Test card for performing assays |
WO1990001564A1 (en) * | 1988-08-09 | 1990-02-22 | Microprobe Corporation | Methods for multiple target analyses through nucleic acid hybridization |
DE68926118T2 (en) * | 1988-08-18 | 1996-08-22 | Au Membrane & Biotech Res Inst | IMPROVEMENTS IN SENSITIVITY AND SELECTIVITY OF ION CHANNEL MEMBRANE BIO SENSORS |
US5096669A (en) * | 1988-09-15 | 1992-03-17 | I-Stat Corporation | Disposable sensing device for real time fluid analysis |
US5200051A (en) * | 1988-11-14 | 1993-04-06 | I-Stat Corporation | Wholly microfabricated biosensors and process for the manufacture and use thereof |
US5063081A (en) * | 1988-11-14 | 1991-11-05 | I-Stat Corporation | Method of manufacturing a plurality of uniform microfabricated sensing devices having an immobilized ligand receptor |
US5219726A (en) * | 1989-06-02 | 1993-06-15 | The Salk Institute For Biological Studies | Physical mapping of complex genomes |
US5143854A (en) * | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
US5750015A (en) | 1990-02-28 | 1998-05-12 | Soane Biosciences | Method and device for moving molecules by the application of a plurality of electrical fields |
US5126022A (en) * | 1990-02-28 | 1992-06-30 | Soane Tecnologies, Inc. | Method and device for moving molecules by the application of a plurality of electrical fields |
ATE131745T1 (en) | 1990-04-11 | 1996-01-15 | Ludwig Inst Cancer Res | METHOD AND DEVICE FOR THE CONSEQUENTIAL CHEMICAL REACTION PROCESS |
US5166063A (en) * | 1990-06-29 | 1992-11-24 | Eli Lilly And Company | Immobolization of biomolecules by enhanced electrophoretic precipitation |
US5527670A (en) * | 1990-09-12 | 1996-06-18 | Scientific Generics Limited | Electrochemical denaturation of double-stranded nucleic acid |
GB2247889A (en) * | 1990-09-12 | 1992-03-18 | Scient Generics Ltd | DNA denaturation by an electric potential |
AU8517391A (en) * | 1990-09-12 | 1992-03-30 | Scientific Generics Limited | Electrochemical denaturation of double-stranded nucleic acid |
US5227265A (en) * | 1990-11-30 | 1993-07-13 | Eastman Kodak Company | Migration imaging system |
WO1992019960A1 (en) | 1991-05-09 | 1992-11-12 | Nanophore, Inc. | Methods for the electrophoretic separation of nucleic acids and other linear macromolecules in gel media with restrictive pore diameters |
US5605662A (en) * | 1993-11-01 | 1997-02-25 | Nanogen, Inc. | Active programmable electronic devices for molecular biological analysis and diagnostics |
US6048690A (en) | 1991-11-07 | 2000-04-11 | Nanogen, Inc. | Methods for electronic fluorescent perturbation for analysis and electronic perturbation catalysis for synthesis |
US5849486A (en) * | 1993-11-01 | 1998-12-15 | Nanogen, Inc. | Methods for hybridization analysis utilizing electrically controlled hybridization |
US6017696A (en) | 1993-11-01 | 2000-01-25 | Nanogen, Inc. | Methods for electronic stringency control for molecular biological analysis and diagnostics |
US5632957A (en) * | 1993-11-01 | 1997-05-27 | Nanogen | Molecular biological diagnostic systems including electrodes |
US5846708A (en) * | 1991-11-19 | 1998-12-08 | Massachusetts Institiute Of Technology | Optical and electrical methods and apparatus for molecule detection |
US5304487A (en) * | 1992-05-01 | 1994-04-19 | Trustees Of The University Of Pennsylvania | Fluid handling in mesoscale analytical devices |
US5312527A (en) * | 1992-10-06 | 1994-05-17 | Concordia University | Voltammetric sequence-selective sensor for target polynucleotide sequences |
US5433819A (en) * | 1993-05-26 | 1995-07-18 | Pressac, Inc. | Method of making circuit boards |
CA2170264A1 (en) * | 1993-09-10 | 1995-03-16 | Michael W. Konrad | Optical detection of position of oligonucleotides on large dna molecules |
US5965452A (en) | 1996-07-09 | 1999-10-12 | Nanogen, Inc. | Multiplexed active biologic array |
US5445525A (en) * | 1994-05-12 | 1995-08-29 | Intel Corporation | Interconnection scheme for integrated circuit card with auxiliary contacts |
US5585069A (en) | 1994-11-10 | 1996-12-17 | David Sarnoff Research Center, Inc. | Partitioned microelectronic and fluidic device array for clinical diagnostics and chemical synthesis |
US5464517A (en) | 1995-01-30 | 1995-11-07 | Bio-Rad Laboratories | Electrophoresis in low conductivity buffers |
US5660701A (en) | 1996-02-29 | 1997-08-26 | Bio-Rad Laboratories, Inc. | Protein separations by capillary electrophoresis using amino acid-containing buffers |
-
1995
- 1995-09-27 US US08/534,454 patent/US5849486A/en not_active Expired - Lifetime
-
1996
- 1996-09-06 JP JP51345297A patent/JPH11512605A/en active Pending
- 1996-09-06 CN CN96198521A patent/CN1202929A/en active Pending
- 1996-09-06 NZ NZ318253A patent/NZ318253A/en unknown
- 1996-09-06 BR BR9610618A patent/BR9610618A/en not_active Application Discontinuation
- 1996-09-06 AU AU69689/96A patent/AU723134B2/en not_active Ceased
- 1996-09-06 WO PCT/US1996/014353 patent/WO1997012030A1/en not_active Application Discontinuation
- 1996-09-06 CA CA 2233238 patent/CA2233238A1/en not_active Abandoned
- 1996-09-06 EP EP96930748A patent/EP0852617A4/en not_active Withdrawn
-
1998
- 1998-08-27 US US09/141,286 patent/US6245508B1/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5252743A (en) * | 1989-11-13 | 1993-10-12 | Affymax Technologies N.V. | Spatially-addressable immobilization of anti-ligands on surfaces |
US5434049A (en) * | 1992-02-28 | 1995-07-18 | Hitachi, Ltd. | Separation of polynucleotides using supports having a plurality of electrode-containing cells |
US5412087A (en) * | 1992-04-24 | 1995-05-02 | Affymax Technologies N.V. | Spatially-addressable immobilization of oligonucleotides and other biological polymers on surfaces |
Non-Patent Citations (1)
Title |
---|
See also references of EP0852617A4 * |
Cited By (81)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6331274B1 (en) * | 1993-11-01 | 2001-12-18 | Nanogen, Inc. | Advanced active circuits and devices for molecular biological analysis and diagnostics |
US7425308B2 (en) | 1993-11-01 | 2008-09-16 | Nanogen, Inc. | Systems for the active electronic control of biological reactions |
US8114589B2 (en) | 1993-11-01 | 2012-02-14 | Gamida For Life B.V. | Self-addressable self-assembling microelectronic integrated systems, component devices, mechanisms, methods, and procedures for molecular biological analysis and diagnostics |
US6468742B2 (en) | 1993-11-01 | 2002-10-22 | Nanogen, Inc. | Methods for determination of single nucleic acid polymorphisms using bioelectronic microchip |
USRE43097E1 (en) | 1994-10-13 | 2012-01-10 | Illumina, Inc. | Massively parallel signature sequencing by ligation of encoded adaptors |
FR2749393A1 (en) * | 1996-05-31 | 1997-12-05 | Motorola Inc | ELECTRODE CONFIGURATION FOR MATRIX ADDRESSING OF A MOLECULAR DETECTION DEVICE |
WO1998051819A1 (en) * | 1997-05-14 | 1998-11-19 | Nanogen, Inc. | Methods for electronic fluorescent perturbation for analysis and electronic perturbation catalysis for synthesis |
US8361713B2 (en) | 1997-05-23 | 2013-01-29 | Illumina, Inc. | System and apparatus for sequential processing of analytes |
EP0985142A4 (en) * | 1997-05-23 | 2006-09-13 | Lynx Therapeutics Inc | System and apparaus for sequential processing of analytes |
EP0985142A2 (en) * | 1997-05-23 | 2000-03-15 | Lynx Therapeutics, Inc. | System and apparaus for sequential processing of analytes |
US9273354B2 (en) | 1997-05-23 | 2016-03-01 | Illumina, Inc. | System and apparatus for sequential processing of analytes |
US8030094B2 (en) | 1997-10-06 | 2011-10-04 | Trustees Of Tufts College | Self-encoding sensor with microspheres |
WO1999018434A1 (en) * | 1997-10-06 | 1999-04-15 | Trustees Of Tufts College | Self-encoding fiber optic sensor |
US7115884B1 (en) | 1997-10-06 | 2006-10-03 | Trustees Of Tufts College | Self-encoding fiber optic sensor |
US9157113B2 (en) | 1997-10-06 | 2015-10-13 | Trustees Of Tufts College, Tufts University | Self-encoding sensor with microspheres |
US7754498B2 (en) | 1997-10-06 | 2010-07-13 | Trustees Of Tufts College | Self-encoding sensor with microspheres |
US8691591B2 (en) | 1997-10-06 | 2014-04-08 | Trustees Of Tufts College | Self-encoding sensor with microspheres |
US8426217B2 (en) | 1997-10-06 | 2013-04-23 | Trustees Of Tufts College | Self-encoding sensor with microspheres |
US7348181B2 (en) | 1997-10-06 | 2008-03-25 | Trustees Of Tufts College | Self-encoding sensor with microspheres |
US6905834B1 (en) * | 1997-11-25 | 2005-06-14 | Ut-Battelle, Llc | Bioluminescent bioreporter integrated circuit detection methods |
US6673596B1 (en) | 1997-11-25 | 2004-01-06 | Ut-Battelle, Llc | In vivo biosensor apparatus and method of use |
US6117643A (en) * | 1997-11-25 | 2000-09-12 | Ut Battelle, Llc | Bioluminescent bioreporter integrated circuit |
KR100591965B1 (en) * | 1997-11-25 | 2006-06-21 | 유티-배텔, 엘엘씨 | Bioluminescent Bioreporter Integrated Circuit |
AU751563B2 (en) * | 1997-11-25 | 2002-08-22 | Ut-Battelle, Llc | Bioluminescent bioreporter integrated circuit |
US7371538B2 (en) | 1997-11-25 | 2008-05-13 | Ut-Battelle, Llc | Microluminometer chip and method to measure bioluminescence |
WO1999027351A1 (en) * | 1997-11-25 | 1999-06-03 | Lockheed Martin Energy Research Corporation | Bioluminescent bioreporter integrated circuit |
US7090992B2 (en) | 1997-11-25 | 2006-08-15 | Ut-Battelle, Llc | Bioluminescent bioreporter integrated circuit devices and methods for detecting estrogen |
US7208286B2 (en) | 1997-11-25 | 2007-04-24 | Ut-Battelle Llc | Bioluminescent bioreporter integrated circuit devices and methods for detecting ammonia |
WO1999027140A1 (en) * | 1997-11-26 | 1999-06-03 | Lockheed Martin Energy Research Corporation | Integrated circuit biochip microsystem |
EP1236807A2 (en) * | 1997-11-26 | 2002-09-04 | Lockheed Martin Energy Research Corporation | Integrated circuit biochip microsystem |
US6197503B1 (en) | 1997-11-26 | 2001-03-06 | Ut-Battelle, Llc | Integrated circuit biochip microsystem containing lens |
EP1236807A3 (en) * | 1997-11-26 | 2004-03-31 | Ut-Battelle, Llc | Integrated circuit biochip microsystem |
GB2346972B (en) * | 1997-11-29 | 2002-09-04 | Secr Defence | Fluorimetric detection system of a nucleic acid |
WO1999028500A1 (en) * | 1997-11-29 | 1999-06-10 | The Secretary Of State For Defence | Fluorimetric detection system of a nucleic acid |
GB2346972A (en) * | 1997-11-29 | 2000-08-23 | Secr Defence | Fluorimetric detection system of a nucleic acid |
US6833257B2 (en) | 1997-11-29 | 2004-12-21 | The Secretary Of State For Defence | Fluorimetric detection system of a nucleic acid |
EP1489190A2 (en) * | 1997-11-29 | 2004-12-22 | The Secretary of State for Defence | Fluorimetric detection system of a nucleic acid |
EP1489190A3 (en) * | 1997-11-29 | 2006-06-07 | The Secretary of State for Defence | Fluorimetric detection system of a nucleic acid |
EP1036085A4 (en) * | 1997-12-05 | 2004-11-17 | Nanogen Inc | Self-addressable self-assembling microelectronic integrated systems, component devices, mechanisms, methods, and procedures for molecular biological analysis and diagnostics |
EP1036085A1 (en) * | 1997-12-05 | 2000-09-20 | Nanogen, Inc. | Self-addressable self-assembling microelectronic integrated systems, component devices, mechanisms, methods, and procedures for molecular biological analysis and diagnostics |
EP0947819A2 (en) * | 1998-03-30 | 1999-10-06 | Hitachi Software Engineering Co., Ltd. | Sample application method and device |
EP0947819A3 (en) * | 1998-03-30 | 2000-09-20 | Hitachi Software Engineering Co., Ltd. | Sample application method and device |
US6251595B1 (en) | 1998-06-18 | 2001-06-26 | Agilent Technologies, Inc. | Methods and devices for carrying out chemical reactions |
US7655129B2 (en) | 1998-06-23 | 2010-02-02 | Osmetech Technology Inc. | Binding acceleration techniques for the detection of analytes |
US9399795B2 (en) | 1998-06-24 | 2016-07-26 | Illumina, Inc. | Multiplex decoding of array sensors with microspheres |
JP2002522065A (en) * | 1998-08-10 | 2002-07-23 | ジェノミック ソリューションズ インコーポレイテッド | Heat and fluid circulation device for nucleic acid hybridization |
US6271042B1 (en) | 1998-08-26 | 2001-08-07 | Alpha Innotech Corporation | Biochip detection system |
WO2000012759A1 (en) * | 1998-08-26 | 2000-03-09 | Alpha Innotech Corporation | Biochip detection system |
US7737088B1 (en) | 1998-08-28 | 2010-06-15 | Febit Holding Gmbh | Method and device for producing biochemical reaction supporting materials |
US7097974B1 (en) | 1998-08-28 | 2006-08-29 | Febit Biotech Gmbh | Support for a method for determining an analyte and a method for producing the support |
US6703228B1 (en) | 1998-09-25 | 2004-03-09 | Massachusetts Institute Of Technology | Methods and products related to genotyping and DNA analysis |
WO2000053311A1 (en) * | 1999-03-11 | 2000-09-14 | Combimatrix Corporation | Self assembling arrays |
WO2000058522A1 (en) * | 1999-03-30 | 2000-10-05 | Nanogen, Inc. | Single nucleotide polymorphic discrimination by electronic dot blot assay on semiconductor microchips |
EP1088101A1 (en) * | 1999-03-30 | 2001-04-04 | Nanogen, Inc. | Single nucleotide polymorphic discrimination by electronic dot blot assay on semiconductor microchips |
EP1088101A4 (en) * | 1999-03-30 | 2004-10-20 | Nanogen Inc | Single nucleotide polymorphic discrimination by electronic dot blot assay on semiconductor microchips |
WO2001042508A2 (en) * | 1999-12-09 | 2001-06-14 | Motorola, Inc. | Methods and compositions relating to electrical detection of nucleic acid reactions |
WO2001042508A3 (en) * | 1999-12-09 | 2002-03-14 | Motorola Inc | Methods and compositions relating to electrical detection of nucleic acid reactions |
US6518024B2 (en) | 1999-12-13 | 2003-02-11 | Motorola, Inc. | Electrochemical detection of single base extension |
US6824669B1 (en) | 2000-02-17 | 2004-11-30 | Motorola, Inc. | Protein and peptide sensors using electrical detection methods |
US7470540B2 (en) | 2000-10-17 | 2008-12-30 | Febit Ag | Method and device for the integrated synthesis and analysis of analytes on a support |
US6492122B2 (en) | 2000-11-09 | 2002-12-10 | Nanogen, Inc. | Quantitative analysis methods on active electronic microarrays |
US7700275B2 (en) | 2001-05-25 | 2010-04-20 | The Secretary Of State Of Defense | Detection system |
US9127308B2 (en) | 2002-03-07 | 2015-09-08 | Atlas Genetics Limited | Nucleic acid probes, their synthesis and use |
US10094800B2 (en) | 2002-03-07 | 2018-10-09 | Atlas Genetics Limited | Assays and apparatus for detecting electrochemical active markers in an electric field |
US8623597B2 (en) | 2002-05-21 | 2014-01-07 | Sony Corporation | Bioassay method, bioassay device, and bioassay substrate |
WO2004011925A1 (en) * | 2002-07-31 | 2004-02-05 | Kabushiki Kaisha Toshiba | Base sequence detecting device and base sequence automatic analyzer |
US7745203B2 (en) | 2002-07-31 | 2010-06-29 | Kabushiki Kaisha Toshiba | Base sequence detection apparatus and base sequence automatic analyzing apparatus |
US7157050B2 (en) | 2002-09-06 | 2007-01-02 | Hitachi, Ltd. | System and method for detecting biological and chemical material |
US7887752B2 (en) | 2003-01-21 | 2011-02-15 | Illumina, Inc. | Chemical reaction monitor |
US8592214B2 (en) | 2003-01-21 | 2013-11-26 | Illumina, Inc. | Chemical reaction monitor |
JP2004271384A (en) * | 2003-03-10 | 2004-09-30 | Casio Comput Co Ltd | Dna analytical device and analytical method |
JP4586329B2 (en) * | 2003-03-10 | 2010-11-24 | カシオ計算機株式会社 | DNA analyzer and analysis method |
WO2004081234A3 (en) * | 2003-03-10 | 2005-07-14 | Casio Computer Co Ltd | Dna analyzing apparatus, dna sensor, and analyzing method |
US7824900B2 (en) | 2003-03-10 | 2010-11-02 | Casio Computer Co., Ltd. | DNA analyzing apparatus, DNA sensor, and analyzing method |
WO2004087303A1 (en) * | 2003-03-28 | 2004-10-14 | Fujitsu Limited | Target detecting device and target capturer, molecule adsorption/desorption device and molecule adsoprtion/desoption method, and protein detecting device and protein detecting method |
EP1588755A1 (en) * | 2003-03-28 | 2005-10-26 | Fujitsu Limited | Target detecting device and target capturer, molecule adsorption/desorption device and molecule adsoprtion/desoption method, and protein detecting device and protein detecting method |
EP1588755A4 (en) * | 2003-03-28 | 2007-05-30 | Fujitsu Ltd | Target detecting device and target capturer, molecule adsorption/desorption device and molecule adsoprtion/desoption method, and protein detecting device and protein detecting method |
US7524672B2 (en) | 2004-09-22 | 2009-04-28 | Sandia Corporation | Microfluidic microarray systems and methods thereof |
US8426135B1 (en) | 2004-09-24 | 2013-04-23 | Sandia National Laboratories | High temperature flow-through device for rapid solubilization and analysis |
US7927546B2 (en) | 2005-10-07 | 2011-04-19 | Anagnostics Bioanalysis Gmbh | Device for the analysis of liquid samples |
US11193922B2 (en) | 2016-10-26 | 2021-12-07 | Roche Sequencing Solutions, Inc. | Multi-chip packaging of integrated circuits and flow cells for nanopore sequencing |
Also Published As
Publication number | Publication date |
---|---|
US5849486A (en) | 1998-12-15 |
EP0852617A4 (en) | 1999-07-28 |
NZ318253A (en) | 2000-02-28 |
BR9610618A (en) | 1999-04-06 |
JPH11512605A (en) | 1999-11-02 |
CA2233238A1 (en) | 1997-04-03 |
AU6968996A (en) | 1997-04-17 |
EP0852617A1 (en) | 1998-07-15 |
CN1202929A (en) | 1998-12-23 |
US6245508B1 (en) | 2001-06-12 |
AU723134B2 (en) | 2000-08-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU723134B2 (en) | Methods for hybridization analysis utilizing electrically controlled hybridization | |
US7704726B2 (en) | Active programmable matrix devices | |
AU702773B2 (en) | Automated molecular biological diagnostic system | |
US7947486B2 (en) | Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics | |
US6099803A (en) | Advanced active electronic devices for molecular biological analysis and diagnostics | |
US6225059B1 (en) | Advanced active electronic devices including collection electrodes for molecular biological analysis and diagnostics | |
US6638482B1 (en) | Reconfigurable detection and analysis apparatus and method | |
US7172864B1 (en) | Methods for electronically-controlled enzymatic reactions | |
AU742960B2 (en) | Advanced active devices and methods for molecular biological analysis and diagnostics | |
JP2001525193A (en) | Self-addressable self-assembled microelectronic integrated systems, component devices, mechanisms, methods and methods for molecular biological analysis and diagnostics | |
US6726880B1 (en) | Electronic device for performing active biological operations and method of using same | |
AU752151B2 (en) | Methods for fingerprinting utilizing an electronically addressable array | |
WO2000032744A9 (en) | Apparatus and methods for transport of charged biological materials | |
De Bellis et al. | Microelectrodes organized in a array format for biomolecular investigations | |
NZ292791A (en) | Automated electronic molecular biological diagnostic system | |
AU5599099A (en) | Method for electronically controlled enzymatic reaction at an addressable location |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 96198521.6 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BR CA CN JP NZ |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
NENP | Non-entry into the national phase |
Ref country code: CA |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 318253 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1996930748 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2233238 Country of ref document: CA Ref document number: 2233238 Country of ref document: CA Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 1997 513452 Country of ref document: JP Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 1996930748 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1996930748 Country of ref document: EP |